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As he was growing up, Herman D. Suit, MD, MSc, PhD, took to heart his mother’s advice: “If you really want something, ask for it politely and repeatedly.” When he was recruited to Massachusetts General Hospital in 1970, he added that the requests not only be polite and repeated, but in writing. By employing that strategy throughout his career—combined with his carefully planned work and the support of numerous friends&mdash;he obtained virtually everything he requested along the way to changing the course of radiation oncology.

During a career that has spanned more than 60 years, Suit helped launch proton therapy as a cancer treatment, introduced preoperative radiation and conservative surgery for patients with soft tissue sarcoma, and developed the intraoperative and preoperative use of electron beam irradiation as methods of reducing the scope of surgical resection.

Along the way, he managed the development of the world-class radiation oncology department at Mass General, was the principal founder of the Connective Tissue Oncology Society and a co-founder of the Particle Therapy Clinical Oncology Group, and served as president of the American Society of Radiation Oncology and the Radiation Research Society.

Throughout his career, Suit has been on a quest to deliver the best care possible to his patients, a mission that includes innovation. “Physicians should view our current best treatment as obsolete and use this as a provocation for active effort to develop superior management strategies,” he wrote in an essay published in 

Born in Houston, Texas, in 1929, Suit distinguished himself academically as an honor student who accelerated his way through the public school system and went on to receive his bachelor of science from the University of Houston in about 2 years. There, he developed a deep interest in organic and biochemistry while taking a course given by Professor Eby Nell McElrath, whom he describes as the most impressive teacher he had—she made the subject truly stimulating to her students, Suit recalled. That led to Suit to plan a career in a medical specialty that was based heavily in science, preferably biochemistry. In 1948, at 19 years of age, he entered Baylor College of Medicine.

In that first year, Suit requested admission into the graduate program so that he could earn a master of science degree in biochemistry as a secondary goal to his studies as a medical student. The chair of biochemistry was not impressed with Suit’s résumé, which listed only freshman-level physics and math. Suit was informed that he would have to take a second year in math and physics at the University of Houston. During his second summer, he was to attend the University of Texas at Austin and take atomic and nuclear physics. Near the end of one of his textbooks, he latched on to a small section that discussed the use of radiation to treat patients with cancer with some impressive success.

“I read this and thought, ‘Golly, that is fantastic!’ I had seen patients who had had their larynx removed in its entirety as their treatment for laryngeal cancer with loss of a critical function—ie, their voice. Apparently, comparable cure results could be achieved by use of radiation alone with clearly superior functional and cosmetic results,” he said.

“So, I became intensely interested about this and rapidly learned more,” Suit said. “I decided to change my goal to a physics-based medical field, vis-à-vis radiation oncology. I was puzzled in that radiation therapy had not been mentioned in any lecture that I had attended at Baylor.”

In his fourth year at Baylor and confident of graduating with his medical and a master of science degrees, Suit faced another decision: where to study radiation oncology. Ever since childhood, he had believed the University of Oxford held one of the highest concentrations of intellect on the planet. The harsh reality, though, was that his family could not afford to send him to England. But a determined Suit applied for a funded position for graduate study, and—to his enormous surprise and pleasure&mdash;his request was granted. He was accepted.

Meanwhile, Suit wrapped up his time at Baylor. Less than 2 months into his rotating internship, he was assigned to administer anesthesia alone to surgical cases, an area in which he’d received minimal instruction. That made Suit extremely nervous. “I had no real training in anesthesia and was scared to death to even try, but had no real option!” he recalls. “Things were much different back then.”

One day early in his internship, while he was providing anesthesia for a thoracic surgical case, the operating room’s head nurse told Suit to go to her office to read a letter that had been sent to him. Suit learned that he was being drafted to serve in the US armed forces and had to report for duty in 2 months—an extremely disappointing development, he said: “I just couldn’t imagine what in the world to do, because I strongly wanted to do research at Oxford.”

He followed his mother’s early advice. “Well, my mother always told me, ‘If you want something, son, you ask for it politely.’ And so I got an appointment with the draft board,” he said. “I went there, and they really had an unfriendly approach toward me. I was just asking for something over which they had absolute control,” Suit said.

Suit stood before the board members to discuss a potential deferment, emphasizing that he wanted to learn about the biological effects of radiation and using it, instead of surgery, as a cancer treatment. He remembered to mention that he had a British fellowship that would cover all his room, board, and living costs. “At that point,” Suit recalls, “the chair of that draft board looked at me with disbelief and shouted, ‘Do you mean that the British are to pay all of the costs of graduate education of an American boy?’ I answered politely, ‘Yes,’ and he slammed his hand on the desk and yelled, ‘Deferment granted!’”

So, after completing his internship, followed by 6 months as a radiation oncology resident, Suit began his doctoral work at Oxford University on January 1, 1954. After several months in clinical residency, he focused on the study of the effects of ionizing radiation on iron metabolism in the blood-forming cells of bone marrow, in vivo and in vitro. He then spent a few months studying clinical radiation oncology before returning to the United States.

“That was one of the most intellectually stimulating times of my life,” said Suit, describing his time at Oxford University. “The chairman of the department would basically say, ‘You don’t believe me, and you don’t believe anybody, when they say something if they do not have supporting data. Otherwise, it’s merely their opinion.’ And opinion was not a complimentary term,” Suit says. “That was a highly challenging and exciting environment.”

Suit anticipated that when he returned to the United States, he very likely would be drafted. Shortly before his departure, during a 3-day visit to the Royal Cancer Hospital in London, he met an American friend who asked, “Herman, why don’t you apply for a deferment and go to a research center like the National Cancer Institute [NCI]?”

“Well, my eyes just lit up at that idea,” Suit said. Once again, he didn’t hesitate to ask for what he wanted. “I applied to join the US Public Health “I lucked out, as there were not many applicants with interest in radiation biology. I enjoyed 2 years of research at the NCI.” Next, Suit was recruited by MD Anderson Cancer Center and stayed there 11 years, from 1959 to 1970. His clinical time was concentrated on patients who had cancer of the bone and connective tissue, assessing the efficacy of preoperative radiation treatment of patients with connective tissue sarcoma. This substantially reduced the need for large surgical margins for subclinical extensions because they could be eradicated by subradical radiation doses. This strategy substantially improved functional status and, in a number of instances, avoided amputation.

Finally, Suit found what might be called his professional home: Massachusetts General Hospital and Harvard Medical School. From 1970 Service and to be assigned to the NCI,”he says to 2000, he served as chief of the Department of Radiation Oncology at the hospital and is now the Andres Soriano Professor of Radiation Oncology, Emeritus, at the medical school. Suit taught and mentored more than 100 residents and research fellows, many of whom went on to chair academic departments.

During those 30 years, Suit was a pioneer both in his research and in advancing Mass General in radiation oncology. In 1973, he initiated the first program to evaluate proton beam radiation therapy as a cancer cure using multiple dose fractions, based at the Harvard Cyclotron Laboratory in Cambridge, Massachusetts. Their physics/engineering team combined with the hospital’s team of physicians and physicists from 1973 to 2001 to develop a proton therapy center in Boston.

All of their work, including the land and part of the cost of the building and machines, was supported by Mass General, combined with generous, sustained funding by grants from the NCI. In 2000, the year before the center went into clinical operation, Suit stepped down as chief at age 71. He was replaced by another faculty member, Jay S. Loeffler, MD.

Suit counts the proton therapy program among his top professional achievements, because it achieved spectacular results for many patients. Proton therapy centers now dot the globe and have treated more than 100,000 patients.

“When you see a patient 10 to 25 years after radiation treatment who is doing well with no cancer and near normal functional results, you can’t have anything except a deep sense of your and the patient’s good fortune,” Suit said. “That’s just natural. So that’s one thing [in my career] that I would put up as highly important.”

When not working, Suit spends time with his wife, Joan, whom he married in 1960. Joan Suit is a Stanford University PhD graduate and retired Massachusetts Institute of Technology research scientist in microbial genetics.

The couple have been avid supporters of educational endeavors. In 2013, the University of Houston honored the couple with the President’s Medallion in recognition of their charitable support. Joan Suit has been a volunteer at the Museum of Science, Boston, where she remains an emeritus trustee.

Suit is confident that the field of radiation oncology will continue to advance and improve in years to come. His prediction for the next 5 to 10 years: “I think we’ll be able to genetically characterize the patient and their tumor so that there will be the ability to design a management strategy for the individual patient.”

Articles

Herman D. Suit, MD, MSc, PhD, a leader in the field of radiation oncology whose innovations lessened the need for radical surgery and improved outcomes for patients, was honored in the Radiation Oncology category with a 2017 Giants of Cancer Care® award.

Persistence and the Quest for Innovation Guided a Radiotherapy Pioneer

Patients with relapsed/refractory non-Hodgkin lymphoma (NHL) have limited options for treatment, and effective advancedstage therapies must be developed for many subtypes of the disease. In the search for solutions, investigators are turning to combination therapies.

The phase IIb UNITY-NHL clinical trial (NCT02793583) is an attempt to determine whether these needs can be addressed using the novel drug umbralisib (TGR-1202) as monotherapy or as part of a doublet or a triplet. The doublet includes ublituximab (TG-1101), and the triplet includes ublituximab and bendamustine (Treanda).

The UNITY-NHL study is enrolling patients with 4 different subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL). Umbralisib is being tested as monotherapy in FL, SLL, and MZL, while the DLBCL subtype is being treated with doublet or triplet therapy. Each lymphoma subtype has its own eligibility criteria, according to Bruce D. Cheson, MD, principal investigator at the Georgetown University Hospital Lombardi Comprehensive Cancer Center in Washington, DC. He said all participants must have relapsed/ refractory NHL that has not responded to standard treatment (

“Each of the settings being studied in this trial is an unmet medical need,” Cheson said. He noted that the nonchemotherapy doublet of umbralisib and ublituximab could prove to be more effective and tolerable than idelalisib (Zydelig), a PIK3δ inhibitor that is approved for patients with relapsed FL or SLL who have received at least 2 prior therapies.

“The study was designed to start with monotherapy treatments and move to combinations in later stages of the trial. The future cohorts will evaluate umbralisib and ublituximab for indolent lymphoma, as well,” said Cheson, who is a professor of medicine, deputy chief of hematology and oncology, and head of hematology and cellular therapy at the Lombardi Comprehensive Cancer Center.

Umbralisib has a unique mechanism of action that makes it a good candidate for combinations and monotherapy. The drug is an orally available PI3Kδ inhibitor that has demonstrated strong activity in numerous preclinical models and in primary cells from patients with hematologic malignancies, according to the drug’s developer, TG Therapeutics in New York, New York. PI3Kδ is strongly expressed in hematopoietic cells and believed to be important in the proliferation and survival of B-cell lymphocytes.

Ublituximab, also developed by TG Therapeutics, is a monoclonal antibody that targets an epitope on the B-lymphocyte CD20 antigen. Anti-CD20 antibodies target and aid in the depletion of B-lymphocytes.

 The chemotherapy bendamustine is a bifunctional mechlorethamine derivative that has shown alkylator and antimetabolite activity. The exact mechanism of action is unknown, but the bifunctional covalent linkage can lead to cell death via several pathways, and the drug is active against both quiescent and dividing cells.

“They all have nonoverlapping mechanisms of action—you’re attacking the cancer in multiple ways at the same time, with potentially improved response over monotherapy,” Cheson said of the 3 agents.

Umbralisib stands out among PI3K inhibitors for its superior safety and tolerability. “Given the track record for prior PI3K inhibitors, we were concerned about severe diarrhea, rash, and opportunistic infections, but we really didn’t see much of that,” Cheson said. “As far as ublituximab goes, the primary reactions are infusion reactions, with very little subsequent consequence. For bendamustine, the myelosuppression, nausea, vomiting, and some immunosuppression are well known.”

In patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and lymphoma (n = 90), umbralisib induced an objective response rate (ORR) of 37%, according to phase I findings published in the 

In the dose-escalation study, 62% of 90 patients experienced reduction in disease burden. The highest response rates occurred in patients with CLL (85%) and FL (53%). Investigators also found that grade 3/4 immune-mediated adverse events (AEs) commonly associated with other PI3Kδ inhibitors were limited—3 patients (<3%) experienced transaminitis, and 2 (<2%) each experienced pneumonia and colitis. The most common treatment-emergent AEs regardless of cause were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).

Promising findings from a study on the combination of umbralisib and ublituximab were presented at the 2017 Congress of European Hematology Association, Madrid, Spain. The study combined the 2 agents with ibrutinib (Imbruvica), and investigators reported that the combination was well tolerated and had activity across heavily pretreated patients with high-risk B-cell malignancies. An ORR of 100% was reached in CLL, mantle cell lymphoma, and MZL, according to slide material presented at the conference. The ORR was 80% in 5 patients with FL, which included 1 complete response (CR) and 4 partial responses (PRs). In DLBCL, just 1 of the 6 patients in the cohort showed a PR, for an ORR of 17%.

A separate study presented in 2017 at the 14th International Conference on Malignant Lymphoma in Lugano, Switzerland, showed that the combination of umbralisib, ublituximab, and bendamustine was safe and highly active in patients with advanced indolent and aggressive NHL, including those not eligible for stem cell transplant or CD19 chimeric antigen receptor T-cell therapy.

In patients with relapsed DLBCL, there was an ORR of 100%, with a 50% CR rate. In patients with refractory DLBCL, there was an ORR of 50% with a CR rate of 42%, with durable responses observed. In patients with relapsed or refractory indolent NHL, there was an 88% ORR with a 50% CR rate. The investigators also concluded that the nonchemotherapy doublet of ublituximab and umbralisib is “a safe and efficacious backbone regimen on which to build novel multidrug combinations.”

 These results served as the rationale for the UNITY-NHL trial.

“There are a lot of novel therapies being developed for lymphoma. We have 3 or 4 PI3K inhibitors, 4 or 5 [Bruton tyrosine kinase] inhibitors, a couple of BCL-2 inhibitors, and a few checkpoint inhibitors,” Cheson said. Based on the strength of prior studies, the doublet and triplet combinations involving umbralisib, ublituximab, and, for some histologies, bendamustine show a lot of promise for addressing the issue “of what is the better way to do things,” he said.

Zydelig [prescribing information]. Foster City, CA: Gilead Sciences, Inc; 2014. accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf. Accessed April 18, 2018.

Umbralisib (TGR-1202). Pipeline. TG Therapeutics website. tgtherapeutics.com/pipeline/TGR-1202.cfm. Updated 2018. Accessed April 17, 2018.

Ublituximab (TG-1101). Pipeline. TG Therapeutics website. tgtherapeutics.com/pipeline/TGTX-1101.cfm. Updated 2018. Accessed April 17, 2018.

Treanda [prescribing information]. Frazer, PA: Cephalon, Inc; 2010. accessdata.fda.gov/drugsatfda_docs/label/2010/022249s005lbl.pdf. Accessed April 17, 2018.

Burris HA 3rd, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. 

 2018;19(4):486-496. doi: 10.1016/S1470-2045(18)30082-2.

Nastoupil L, Lunning MA, Vose JM, et al. Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL. Abstract presented at: 22nd Congress of European Hematology Association; June 22-25, 2017; Madrid, Spain. Abstract S772. learningcenter.ehaweb.org/eha/2017/22nd/182059/loretta.nastoupil.chemo-free.triplet.combination.of.tgr-1202.ublituximab.and.html?f=media=3.

Lunning M, Bierman PJ, Bociek RG, et al. Combination of TGR-1202, ublituximab, and bendamustine is safe and highly active in patients with advanced DLBCL and follicular lymphoma. Poster presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. tgtherapeutics.com/U2%20Benda%20ICML%20Final.pdf.

The phase IIb UNITY-NHL clinical trial is exploring the novel drug umbralisib as monotherapy or as part of a doublet or a triplet. The doublet includes ublituximab and the triplet includes ublituximab and bendamustine.

Promising Umbralisib Combinations Tested in NHL Subtypes

For the past 18 months, 187 oncology practices across the United States have been participating in the Oncology Care Model (OCM), the Center for Medicare & Medicaid Innovation (CMMI) program designed to provide higher-quality, more coordinated cancer care at the same or lower cost to Medicare beneficiaries. In this complex program, treatment is divided into 6-month episodes of care, and practices receive quarterly installments of claims data from the Centers for Medicare & Medicaid Services (CMS). Practices are only just receiving their first reconciliation reports from CMS for treatment delivered at the very outset of the OCM. The first few reconciliation reports will be critical, as they will indicate whether a practice can save money and still provide quality care― both of which must occur to succeed in this model.

Sixteen practices in The US Oncology Network (The Network) are participating in the OCM. At this point, it is not known how many―or whether any―of our practices will succeed. Some may not receive a performance-based payment, issued for meeting quality and value thresholds, the first time around. This would not be very surprising because this is considered a “ramp-up” period. Hopefully, for the second performance period, which is already complete, practices will show they can reduce total expenditures compared with what they were predicted to spend, even if they were unsuccessful in cutting costs in the first round. Unfortunately, CMS’ reconciliation reports for the second period will not be available for another 6 or 7 months.

Keys to OCM Success Although there are still many unknowns with the OCM, a few conclusions can be drawn based on what is known about the model. Essentially, there are 5 crucial activities for success. If any of these activities is not done well, the practice probably will not succeed with the program.

1. Identifying patients and billing for monthly-enhanced oncology services (MEOS)

Patients eligible for the program must be identified before they can be enrolled in the OCM and undergo treatment. This may sound easy, but it is difficult to accomplish. Practices must develop workflows to identify OCM-eligible patients. Particularly challenging is identifying patients on oral drugs, as it is hard to know whether an oral cancer medication was prescribed if it was not documented clearly in the electronic medical record. In addition, a practice must have an initial fill date to mark the start of a chemotherapy episode. Patients who receive intravenous treatment are easier to track because the clinic controls drug administration and documentation is more evident. All eligible patients must be enrolled in the OCM— patients can decline participation in the OCM, but the practice can’t pick and choose.

New processes must be established to bill Medicare for the enhanced services offered to patients. The practice may need to hire social workers, navigators, and other staff to deliver these additional services and follow through on program requirements, such as adherence to the Institute of Medicine’s Care Management Plan. Much to Medicare’s credit, the up-front funding needed to accomplish practice transformation is provided in the form of MEOS payments. Without this money, offering unbillable services such as navigation, nutrition, and social work would not be possible in a community cancer care delivery setting. It is still uncertain whether the OCM design will be financially viable for community practices, but the 16 participating practices within The Network are interested in finding out.

2. Performing and reporting on all quality metrics

If practices do not report their data to Medicare, this metric will not be factored into their performance scores. Data must be submitted through the OCM portal and include detailed information about enrolled patients such as cancer stage. Whereas the first performance period required practices to report on quality metrics, the second period required them to improve on those metrics. Practices now must report and perform to succeed in the OCM.

In addition to the metrics submitted by practices, quality measures based on CMS claims data are used to judge practice performance. One of the important measures in this group is how well practices succeed in reducing hospital visits; practices must perform on this metric to achieve points toward their Aggregate Quality Score.

3. Passing audits and other on-site visits

CMS may visit practices to verify that the requirements and intent of the program are being followed. There are requirements for “redesign activities” that must be met. These activities can make a difference in the patient’s cancer care journey, so fulfilling these requirements is imperative to satisfying the terms of the program, not only to pass a potential audit but also to support optimal outcomes. Practices that fail an audit could be removed from the program, even if they are saving money and reporting satisfactorily on quality metrics.

4. Ensuring appropriate cost resource utilization

Cost resource utilization is Medicare’s term for the proper management of MEOS payments to ensure the money is being used to fund enhanced services. To verify funds are being spent appropriately, all practices must submit data on Medicare’s cost resource utilization website. Practices must enter detailed information concerning all new employees— including salary information&mdash;who are integral to the OCM. The MEOS money must, at least in part, go to new hires, as the premise is that practices cannot provide enhanced services without increasing their existing workforce. Practices must also submit information on any existing employee who is doing a component of work for the OCM that he or she was not doing before. This information should include how much time is spent on OCM activities.

This is one of the most crucial elements of the program, as the management of costs is a core component being evaluated in the OCM. CMS and CMMI are watching the program carefully to see whether it can deliver better, more cost-efficient cancer care to Medicare beneficiaries. In other words, fulfilling CMMI’s Triple Aim: better care, healthier people, and smarter spending.

If practices successfully complete the first 4 keys to success but spend an exorbitant amount of money providing care, they will fail to meet the criterion of controlling costs. Not only will they not receive performance-based payments, but they will ultimately fail the program.

Feedback from patients in the OCM across The Network has been positive, as they have seen an improvement in the way their care has been delivered. Providers are also generally enthusiastic about participating in this novel program, despite the additional workload and practice transformation required.

The OCM is not for all practices, but if a practice believes in what the model is trying to achieve—and the experience has been fairly positive so far&mdash;it should be worthwhile to remain in the program. Conversely, if it is burdensome for the practice and difficult to master, it might be wise to discontinue.

Practices not in the OCM are participating in the Merit-based Incentive Payment System, another federal value-based reimbursement program. One way or another, the government is determined to focus on value, and these types of programs are not going away. The OCM is merely a stepping-stone to the future, and oncology practices must adapt to this new way of doing business and delivering care.

Marcus Neubauer, MD, discusses the tools needed for a practice to succeed with the Oncology Care Model.

5 Key Elements Needed to Achieve Success With the Oncology Care Model

The dramatic surge in hospital merger and acquisition activity that gobbled up oncology practices by the score is losing steam as a result of numerous policy and legislative acts, and this is creating a climate of uncertainty in terms of revenue generation, according to Michael L. Blau, JD, of Foley & Lardner. The repercussions of these changes are affecting not just the prospects for independent oncology practices but also the ability of inner-city and charity-care hospitals to continue serving low-income residents to the extent that they have in the past.

Since 2008, 423 individual cancer treatment sites have closed, often because of competitive pressures caused by policies and legislation that favored large hospital treatment centers, and another 658 community cancer centers were acquired by or became affiliated with hospitals, according to the Community Oncology Alliance. Many hospital acquisitions and alignments have been driven by shared-service agreements and co-management arrangements that allowed increased returns of up to 10% to 15%, Blau said in remarks at the 2018 Association of Community Cancer Centers 44th Annual Meeting and Cancer Center Business Summit, held in March in Washington, DC. Such margins will be much slimmer going forward, and some financial “downside” can be expected, he said.

Blau moderated a panel of experts who discussed practice alignment activities from different perspectives, including how to derive organizational synergy from patient-centered care, integrate operations to prevent disjointed care, and negotiate an alignment deal that works for both sides.

The past few years have seen a number of measures implemented that put the brakes on the rapid consolidation of practices and the upward spiral in costs of cancer care borne by the Centers for Medicare & Medicaid Services (CMS).

Medicare site neutrality rules curtailed the practice of hospitals acquiring lower-cost treatment centers to extend higher hospital outpatient department rates to those facilities. Revisions in CMS reimbursement rates for drugs purchased through the 340B Drug Pricing Program are expected to significantly lower revenues for some providers in the discount program, although the $1.6 billion in savings will be reinvested in healthcare. The Merit-based Incentive Payment System (MIPS) rewards or penalizes oncology practices based on the extent of improvements in quality and value of care (

), and the Tax Cuts and Jobs Act of 2017 is expected to move millions of covered individuals into situations in which they rely on free or reduced-price care, adding to the pressure on urban hospitals and other charity providers (

“The net effect is less money to support physician- alignment arrangements, and this is what was really driving consolidation over the last 10 to 15 years,” Blau said. He noted that further developments are expected to compound the revenue pressure. In 2019, oncology practices will face upward or downward 4% Medicare payment adjustments based on their MIPS performance, and those adjustments will expand to plus or minus 9% by 2022. Some may have chosen to sidestep MIPS by enrolling in the Oncology Care Model experiment, but those practices are also under pressure to reduce costs.

There are still opportunities for gain, Blau noted. Despite the outpatient payment rate changes, it's still allowable for oncologists to move their practices onto hospital sites and receive the higher payment rates from CMS. In addition, although reductions are planned in 340B payments, a redistribution of the savings is expected to improve revenues for a large swath of hospital providers.

Challenges in Consolidation Tulsa Cancer Institute (TCI) was one of the largest independent practices in Oklahoma when it merged with St John Health System in 2016 and became Oklahoma Cancer Specialists and Research Institute (OSCRI). The deal occurred shortly after TCI had built a new cancer facility in an expansion of its operations. There were synergies at the outset but also challenges to making the merger a success, said Jason Ervin, MBA, of OCSRI.

The group saw a huge influx of patients who had previously been seen by the hospital providers. In a short time, 1800 hospital patients began using the outpatient facilities, and the staff had to incorporate hospital records into an electronic health record system that was not capable of managing this process without heavy manual input, Ervin said. These new patients had more comorbidities and financial challenges, which amounted to the biggest challenge of making the merger work. “We worked to enhance the infrastructure for low- or no-pay patients,” he said. The number of wheelchairs had to be tripled.

Throughout it all, they kept the focus on quality, and they have the positive patient satisfaction surveys to prove that they were successful at this, Ervin said. He added that the partnership improved relationships with hospital staff and with affiliates of the hospital with whom they may have been in competition before.

Table. Actions Expected to Reduce Hospital-Oncology Practice Mergers

The joint venture that created OSCRI made it a provider-based organization with physicians as the majority owners and managers. The group is an Oncology Care Model participant and also participates in 3 other value-based care models with varying requirements, which presents many data integration challenges, although OSCRI “believes participating in these models is crucial,” Ervin said.

Whereas Ervin described a participatory merger in which physicians were financially motivated to make the realignment of operations a success, George Daneker Jr, MD, chief medical officer of Cancer Treatment Centers of America (CTCA), said that CTCA has sought to nurture talent by discovering it within or outside the healthcare organization and then providing thorough training to instill leadership and management skills in those individuals. It’s also important to match talent with skilled leadership so that the process of mentoring and collaboration develops opportunities into success. This produces results, Daneker said: “I’ve found that physicians have great ideas, but when I say, ‘How are you actually going to do that?’ they say, ‘Uh, I don’t know. Give it to somebody else, and I’ll come back in a couple of months and see if it’s done.’”

Another issue that needs to be addressed within a merger environment is the coordination of care. Daneker said it is often the case that components of care are good but not well coordinated. Patients complain about this. “For a patient with a cancer diagnosis, minutes are like hours, and hours are like days.” CTCA has multiple locations spread across 3 time zones, so coordination problems can make it frustrating to deliver the quality of care that hospital administrators would like, he said.

Like Ervin, Daneker said the key has been to keep the focus squarely on the patient, and in doing so, the multiple parts of the cancer treatment delivery network begin to function in a coordinated manner. At CTCA, this is accomplished in part by giving patients a 27-question survey that lets them describe what they’re experiencing as a result of their disease and their treatment. The automated survey is designed to ping physicians if any trouble signs appear—problems that a patient might not report independently until conditions become more serious and costly to treat.

Another key to delivering the value that patients had asked for was the development of cross-functional teams that can deliver care that patients feel is tailored to their particular cancer. These specialists are linked and informed by tumor boards, case conferences, and other meetings. In addition, a significant effort has been made to simplify clinical pathway information on 670 different regimens so that physicians find them understandable and easy to use and the same information can be understood by patients, which facilitates doctor— patient discussions, Daneker said.

As cancer treatment becomes more targeted and consequently more complex, simplification serves a growing need among oncologists for practical guidance that cuts through the clutter. Daneker said the following comment sums up the mood among a large proportion of oncologists: “Genomics scares the hell out of me. There’s just so much stuff. I don’t know how I’m going to integrate it into my practice.”

There’s more to the success of an integration among healthcare providers than a patient focus, and whereas external factors such as regulatory strictures may play a role, there’s no substitute for good planning and execution, said Kelley D. Simpson, MBA, of Oncology Solutions, an Atlanta, Georgia—based consulting firm. Well-structured agreements include careful oversight, performance metrics, and planning. She presented a hypothetical business case of a healthcare system that contracted with a physician practice to clinically comanage the oncology service line.

“Don’t underestimate the time you need to plan and go live. That’s probably where things go awry most often and where there’s the most confusion and disappointment between the parties,” Simpson said. In a tactical timeline she presented, 3 months were set aside at the outside for the groundwork of engaging consultants, a valuation firm, and legal counsel and for defining service line components. A subsequent 3 months were set aside for discussion of quality and performance metrics and finalizing valuation and letters of intent. Six to 9 months after initiating the process, both parties should be discussing financial terms and operational arrangements. At 10 months comes the approval to go live, in accord with testing and tracking; following that, parties to the deal should monitor carefully and refine processes to ensure that the consolidation is a success.

“We recommend a working group that includes hospital leadership and the physician practice and leadership to really work on what the reporting structure is going to be—meetings, tracking and reporting performance improvement and quality improvement activities and then test that for a month or two and then go live,” Simpson added.

Payment to physicians and staff should be calibrated to avoid paying twice for the same task, such as an administrative task that is also recognized as a performance-based service. Good collaborative deals are defined by well-delineated tasks, which means that responsible parties need to be identified from the outset and boundaries should be maintained. Be careful not to let hospital-based staff and time cross over to physician-designated performance deliverables,” Simpson said. n

Community Oncology Alliance. 2018 Community Oncology Alliance practice impact report. communityoncology.org/downloads/pir/ COA-Practice-Impact-Report-2018-FINAL.pdf. Published April 2018. Accessed April 19, 2018.

Since 2008, 423 individual cancer treatment sites have closed and another 658 community cancer centers were acquired by or became affiliated with hospitals.

The Looming Squeeze on Provider Revenues

Major changes for patients with HER2- positive breast cancer are not on the horizon, but there are a number of new study findings that have amplified knowledge about how best to care for this population.

Dual-Targeted Neoadjuvant Therapy: Pertuzumab Plus Trastuzumab With Chemotherapy

That was the consensus of a panel of breast cancer oncologists who participated in an

 discussion of research presented at the San Antonio Breast Cancer Symposium (SABCS), held December 5 to 9, 2017, in Texas. These experts reviewed key abstracts on HER2+ breast cancer and provided perspectives on how studies of systemic therapy in this setting may influence clinical practice. Despite many advancements in the past 2 decades, the HER2-positive subtype presents challenges. Metastatic HER2- positive breast cancer remains incurable and represents an unmet medical need.

Adam M. Brufsky, MD, PhD, session moderator, began the discussion by observing that interesting abstracts at SABCS covered both early and late disease. Neoadjuvant therapy in HER2-positive breast cancer has been a tremendous success, he said, noting research on determining the optimal chemotherapy backbone for using neoadjuvant trastuzumab (Herceptin) plus pertuzumab (Perjeta).

Trastuzumab (H) and pertuzumab (P) is approved as a standard neoadjuvant therapy for stage II to III HER2-positive breast cancer. Francisco J. Esteva, MD, PhD, discussed a singlecenter, retrospective study that evaluated chemotherapy used with neoadjuvant pertuzumab- containing regimens in this setting.

The study evaluated rates of pathologic complete response (pCR) in 226 patients with stage II to III HER2-positive breast cancer who received neoadjuvant trastuzumab plus pertuzumab (PH) in combination with backbone chemotherapies that included a taxane (T), an anthracycline and cyclophosphamide (A), or carboplatin (C). Combination therapies included paclitaxel, trastuzumab, and pertuzumab (THP) and docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP).

The pCR rates were 65% for THP (n = 48), 50% for TCHP (n = 90, including 5 who received TCHP-A), and 58% for THP-A (n = 88); these differences were not statistically significant. Esteva said it was reassuring that THP did not result in a lower pCR rate than TCHP or THP followed by adjuvant chemotherapy.

“How those patients were selected, though, and why is the question,” he commented. “It’s something to keep in mind—that some patients may do very well with THP, like they did in the NeoSphere trial, which was the FDA registration trial for pertuzumab.” In the phase II NeoSphere trial (NCT00545688), patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned to neoadjuvant H plus docetaxel (HT), docetaxel plus HP (THP), HP, or P plus docetaxel (PT).

 After surgery, patients received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy. The study showed that progression- free survival (PFS) rates were highest for the groups receiving THP or HT.

Patients who experienced pCR after any neoadjuvant combination had longer PFS. If patients experience pCR on neoadjuvant therapy, Esteva said, they might not need FEC after surgery. However, because patients received THP, then surgery, and then FEC, the pCR rates without adjuvant chemotherapy are unknown.

Hope S. Rugo, MD, pointed out that in the APHINITY trial (NCT01358877) of pertuzumab added to adjuvant trastuzumab and chemotherapy,

 as well as in the NeoSphere trial, the rates of grade 3 diarrhea are high. Using weekly paclitaxel plus trastuzumab plus pertuzumab is much better tolerated, Rugo said. “The idea is, less is more,” she continued. After induction therapy and response evaluation, additional therapy could be selected for patients based on tumor characteristics and tolerance. Rugo said that she thinks that weekly paclitaxel with THP is a better choice than docetaxel for older patients, and Komal Jhaveri, MD, noted that neutropenia is a serious adverse effect with docetaxel. Brufsky and Lee Schwartzberg, MD, said that they administer growth factors to all their patients with breast cancer because of the risk of neutropenia.

Schwartzberg expressed comfort with using docetaxel in older patients, although weekly paclitaxel is an option for patients with low-risk disease. Esteva administers weekly THP for 12 weeks, followed by dose-dense adjuvant chemotherapy before surgery, noting that some patients might not need it, but it’s difficult to tell. Because of toxicity, he said, he doesn’t like administering docetaxel or carboplatin.

Rugo says that her practice administers paclitaxel first, then 4 doses of pertuzumab, followed by dose-dense adjuvant chemotherapy. “But now, if somebody has a pCR essentially by exam and imaging after their THP, it’s hard to give them adjuvant chemotherapy, especially for older patients,” she added.

Schwartzberg still administers anthracyclines; so does Jhaveri. “It’s hard to say a nonanthracycline regimen is better, but they’re probably comparable,” Schwartzberg said. “The thing that I worry about, actually, is tumor heterogeneity and whether we should be giving adjuvant chemotherapy for those patient populations that have variable HER2 in their tumor, particularly larger tumors where there’s more likelihood [of heterogeneity].”

The use of tyrosine kinase inhibitors (TKIs) such as neratinib (Nerlynx) and lapatinib (Tyverb) as neoadjuvant therapy in HER2- positive breast cancer was presented at SABCS.

 The panelists said they would not use TKIs off-label for neoadjuvant therapy at this time. Not a lot of data support this use, Brufsky said, and despite a slightly increased pCR rate, no survival benefit has been demonstrated.

However, Rugo said that in estrogen receptor (ER)—positive disease, if patients have received a year of pertuzumab and have gastrointestinal distress, neratinib might be an option. The randomized phase III ExteNET trial (NCT00878709) compared 1 year of neratinib, a pan-HER TKI, with placebo after neoadjuvant and adjuvant chemotherapy plus trastuzumab in 2840 women with nonmetastatic, operable HER2-positive breast cancer.

At 5 years of follow-up, extended adjuvant therapy with neratinib significantly reduced clinically relevant relapses versus placebo.

Treatment of neratinib-associated diarrhea was the subject of another abstract presented at SABCS, which showed that loperamide reduced the incidence, severity, and duration of neratinib-associated diarrhea and that adding budesonide or colestipol (Colestid, Cholestabyl) further reduced duration and number of episodes (CONTROL study, NCT02400476).

The issue of de-escalation of treatment in HER2+ early breast cancer was examined in the Synergism Or Long Duration (SOLD) study (NCT00593697), a follow-up of the FinHer trial in which 3 weekly doses of docetaxel were administered in place of weekly paclitaxel, FEC was administered in place of AC, and trastuzumab was administered continuously with docetaxel for 9 weeks.

 Determining whether 9 weeks of trastuzumab could be used rather than the standard 12 months was an important question, Rugo said, because the optimal duration of trastuzumab is not known and because of its cost. “Most people in the world can’t afford trastuzumab,” she said. “Now, with the advent of biosimilars, we hope that that will change, but we have yet to see what the cost differentials will be and what the impact will be.”

Rugo characterized 9 weeks as a “funny choice,” however—9 weeks of trastuzumab did not meet noninferiority to 12 months. In a subgroup analysis, patients who received 100 mg/m

 of docetaxel, which she called a toxic dose, did as well with 9 weeks of trastuzumab, as did patients with lowerrisk disease. “I think we’re a little encouraged by the fact that shorter may be enough for some patients, and that some trastuzumab is better than none. But our gold standard is still 12 months. Now, how long should you get pertuzumab for? We don’t know,” she said.

Trastuzumab Plus Adjuvant Chemotherapy in Low HER2 Expression

Schwartzberg said that risk must be weighed against benefit, and for trastuzumab, toxicity outweighs the benefit of extended therapy. There is room for de-escalation, Jhaveri said, and that should be the focus of biomarker studies. Rugo said that it will be important to determine which patients will require more therapy based on tumor response. Schwartzberg responded, “pCR is such a good biomarker in HER2-positive [breast cancer], so why not use it to either de-escalate or escalate?”

In the NSABP B-31 trial, Brufsky said, an unplanned subset analysis showed that patients with tumors that had low expression levels of HER2 still benefited from trastuzumab. At SABCS, investigators presented results of a phase III study, NSABP B-47, that looked prospectively at adjuvant trastuzumab for 3270 women with low-level HER2-expressing invasive breast cancer.

 Adding trastuzumab did not provide a benefit in patients with HER2- nonoverexpressing breast cancer. Schwartzberg commented that the trial results confirm that HER2 is a target for trastuzumab therapy. The 5-year disease-free survival rate was 90% and could be attributed in part to the high percentage of women in the trial with ER-positive disease who, Brufsky said, would do well no matter what therapy they received. The panelists all follow American Society of Clinical Oncology/College of American Pathologists guidelines

Immunotherapies are being tested in breast cancer. Rugo pointed out that although breast cancer is not very immunogenic, it increasingly affects the host immune system as it progresses. SABCS also saw results of the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) phase Ib/II study (NCT02129556), which evaluated the safety and efficacy of pembrolizumab, an anti—PD-1 immune checkpoint inhibitor, in combination with trastuzumab in patients with trastuzumab-resistant, metastatic, HER2- positive breast cancer.

The disease control rate was 24% in PD-L1—positive disease. In this early trial in 58 patients, tumor-infiltrating lymphocytes were low, which is expected as cancer progresses, and were identified as a potential predictive marker of response. Rugo suggested that adding agents to immunotherapy that would boost host response could help, but this would need to be done early in the disease course.

Schwartzberg pointed out that PD-L1 is expressed at lower levels than in other tumor types, calling the data for pembrolizumab in the neoadjuvant I-SPY 2 trial

 “very impressive.” This study identified gene expression signatures associated with response to pembrolizumab and higher pCR rates.

Also at SABCS, results of a phase I study of an antibody—drug conjugate targeting HER2 expression were reported.

 The agent, trastuzumab deruxtecan (DS-8201), a humanized HER2 antibody attached to a novel topoisomerase I inhibitor, was administered to several cohorts of patients, including those with HER2-positive breast cancer who had previously received ado-trastuzumab emtansine (T-DM1; Kadcyla) and patients with breast cancer expressing low levels of HER2. The overall response rate in the HER2-positive patients was 61%; it was 30% in the HER2—low expression group, which included patients with ER-positive, HER2-negative, and triple-negative disease. Jhaveri commented that the duration of response was impressive. Trastuzumab deruxtecan has been designated a breakthrough therapy by the FDA.

Hurvitz SA, Gelmon KA, Tolaney SM. Optimal management of early and advanced HER2 breast cancer. 

2017;37:76-92. doi: 10.14694/EDBK_175630.

Rashmi MK, Akshara RS, Kenneth HR, et al. Patterns of use and effectiveness of neoadjuvant pertuzumab-containing regimens in stage II-III HER2-neu positive breast cancer: a retrospective, single institutional experience. Poster presented at: 2017 SABCS; December 5-9, 2017; San Antonio, TX. Poster P5-20-10.

Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant per3. tuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. L

 2016;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7.

von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. 

2017;377(2):122-131. doi: 10.1056/NEJMoa1703643.

Krop IE, Hillman D, Polley M-Y, et al. Invasive disease-free survival and gene expression in CALGB (Alliance) 40601, a randomized phase III neoadjuvant trial of dual HER2-targeting with lapatinib added to chemotherapy plus trastuzumab. Abstract presented at: 2017 SABCS; December 5-9, 2017; San Antonio, TX. Abstract GS3-02.

Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(120):1688-1700. doi: 10.1016/S1470-2045(17)30717-9.

Hurvitz S, Chan A, Iannotti N, et al. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: the CONTROL trial. Poster presented at: 2017 SABCS; December 5-9, 2017; San Antonio, TX. Poster P3-14-01.

Joensuu H. Escalating and de-escalating treatment in HER2-positive early breast cancer. 

 2017;52:1-11. doi: 10.1016/j.ctrv.2016.11.002.

Joensuu H, Fraser J, Wildiers H, et al. A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant taxane-anthracycline chemotherapy, for early HER2-positive breast cancer (the SOLD study). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS3-04.

Fehrenbacher L, Cecchini RS, Geyer CE, et al. NSABP B-47 (NRG Oncology): phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FHISH (HER2-Low IBC). Abstract presented at: SABCS; December 5-9, 2017; San Antonio, TX. Abstract GS1-02.

Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice Guideline update. 

2013;31(310):3997-4013. doi: 10.1200/JCO.2013.50.9984.

Loi S, Giobbe-Hurder A, Gombos A, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic breast cancer: results from the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) study. Presented at: 2017 SABCS; December 5-9, 2017; San Antonio, TX. Abstract GS2-06.

Campbell M, Yau C, Borowsky A, et al. Analysis of immune infiltrates (assessed via multiplex fluorescence immunohistochemistry) and immune gene expression signatures as predictors of response to the checkpoint inhibitor pembrolizumab in the neoadjuvant I-SPY 2 trial. Poster presented at: 2017 SABCS; December 5-9, 2017; San Antonio, TX. Poster PD6-08.

Modi S, Tsurutani J, Takahashi S, et al. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. Presented at: 2017 SABCS; December 5-9, 2017; San Antonio, Texas. Abstract PD3-07.

A panel of experts discuss the latest developments in the treatment of patients with HER2-positive breast cancer.

Findings Clarify Picture for HER2-Positive Breast Cancer

Components of the T-cell receptor (TCR) complex, which links antigen recognition with T-cell activity and effector function, are being exploited for several types of cancer immunotherapy. Although these strategies have not received the same level of attention as blockbuster immunotherapies such as checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies, they have made steady progress over the past few years, and many novel agents are undergoing clinical testing.

Broadly speaking, investigational therapies that target the TCR are being developed in 3 categories: TCR-engineered T cells, bispecific antibodies, and immune-mobilizing monoclonal T-cell receptors (ImmTACs).

TCR-engineered T cells are an alternative form of adoptive cell therapy (ACT). These therapies redirect the specificity of the TCR against tumor-associated antigens (TAAs) to target intracellular antigens, where CAR T cells are only just beginning to venture. Stateof- the-art genetic engineering techniques such as CRISPR have the potential to fine-tune these therapies more precisely.

Bispecific antibodies target both tumor cells and T cells via the CD3 component of the TCR complex. Clinical development has yielded FDA approval of the first-in-class drug blinatumomab (Blincyto) for the treatment of patients with acute lymphoblastic leukemia (ALL). Recent expansion of its approved indications offers a new option for patient populations with few therapeutic avenues.

Researchers also are working on ImmTACs, a new class of bispecific drugs that combines the advantageous properties of targeting intracellular antigens and the benefits of a soluble drug format without the time-consuming and labor-intensive manufacturing requirements of cell-based therapies.

As our understanding of the dual role of the immune system in both restraining and promoting cancer has evolved, so too has our ability to harness its components to yield groundbreaking therapies that augment the antitumor immune response and offer the promise of long-lasting tumor regression.

The focus of cancer immunotherapy has been on mobilizing cytotoxic T cells, the central mediators of cell-mediated adaptive immunity. T cells are activated by protein fragments derived from pathogens that are displayed on the surface of antigen-presenting cells (APCs), such as macrophages, bound to major histocompatibility complex (MHC) molecules.

Although cancers are derived from the body’s own cells gone awry and, in theory, should not stimulate an immune response, the accumulated genetic alterations that often drive cancer can generate unique proteins that T cells recognize and by which they are activated. Tumor antigen—specific T cells, known as tumor-infiltrating lymphocytes (TILs), can be identified in most tumor types.

In response, cancer cells have evolved a multitude of mechanisms to suppress TIL activity and tip the balance of power to the tumor. The idea of immunotherapy is, therefore, to restimulate the antitumor immune response and wrestle back that control. Two major strategies for manipulating T cells have proved particularly effective: immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway and CTLA-4 and genetically engineered CAR T cells.

T-cell activation is dependent on the TCR upon its surface, which engages the antigen-MHC complex on APCs, triggering a cascade of signaling molecules within the cell that ultimately promotes the proliferation of T cells and the acquisition of the properties that enable their effector functions.

This downstream signaling is a highly complex branched network of events that is still not fully understood but maintains a precisely set threshold of activation, ensuring that T cells are switched on only at the appropriate time and for only as long as necessary.

The TCR is a member of the immunoglobulin superfamily and consists of a heterodimer of 2 highly variable protein chains (

). In most cases, those protein chains are encoded by the 

genes. In 5% of cases, the TCR instead is composed of TCRδ and γ chains, although these percentages can change in certain circumstances, such as during T-cell development. Each TCR possesses unique antigen specificity thanks to their random assembly of different gene segments.

  The constituent protein chains are made up of a variable and constant region that protrudes from the cell, a portion that spans the membrane, and a short tail inside the cell. Unlike most transmembrane receptors, the tail of the TCR has no inherent signaling activity. Instead, the TCR forms a complex with the CD3 protein family consisting of CD3δ, γ, ε, and ζ, which link the antigen recognition abilities of the TCR with the activation of downstream signaling pathways.

Upon binding of the TCR by the antigen, the SRC family tyrosine kinase LCK is activated. LCK phosphorylates key signaling domains within CD3ζ, known as immunoreceptor tyrosine- based activation motifs (ITAMs), which serve as a binding platform for zeta chainassociated protein kinase 70 (ZAP70), which is also phosphorylated and activated by LCK and goes on to phosphorylate a range of adapter proteins, further propagating the signal by triggering a number of key pathways (

T cells require 2 signals to become fully activated, providing another safety check mechanism to prevent damage to healthy tissues. A number of transmembrane receptors play important roles in providing this essential costimulatory signal, including CD28 and CTLA-4, which are among the targets for immune checkpoint inhibitor drugs.

Figure 2. A View of How the TCR Activates Immune Signaling

Alongside immune checkpoint inhibitors at the forefront of cancer immunotherapy, CAR T cells are a form of ACT that involves harvesting the patient’s T cells, culturing them outside the body, and then reinfusing them into the patient. Although they have dominated this field, genetic manipulation of the TCR is also being explored to generate TCR-engineered T cells.

This type of therapy is limited by the fact that the TCRs must be genetically matched to the patient’s immune type but offers a significant advantage over CAR T cells. The latter are antibody based and can recognize only cell surface antigens; the number of unique TAAs expressed on the cancer cell surface is small. TCR-engineered T cells can recognize intracellular proteins that have been processed and presented by APCs, which greatly broadens the scope of potential targets. The TCR can also be manipulated to improve its antigen recognition and binding capabilities.

 It should be noted that CARs targeting intracellular antigens are also being explored.

A number of experimental therapies are under evaluation in clinical trials (

). The cancer testis antigens have provided a particularly important source of potential targets; the group of proteins is restricted in expression to the testis, except during cancer development. Among them are the melanomaassociated antigen (MAGE) proteins and NY-ESO-1; the latter holds particular interest because it is one of the most highly immunogenic antigens ever discovered. Other targets that are being explored include melanoma antigen recognized by T cells (MART-1), glycoprotein 100 (gp100), and various virally associated antigens.

Initial studies have demonstrated early successes in certain tumor types.

 Six of 20 patients treated with T cells with a highaffinity TCR engineered to recognize MART-1 had tumor regression.

Meanwhile, a study using a high-avidity TCR recognizing the NY-ESO-1 antigen demonstrated objective clinical responses in 4 of 6 patients with synovial sarcomas and 5 of 11 patients with melanoma.

In a separate study, in patients with multiple myeloma, NY-ESO-1- specific TCR-engineered T cells elicited clinical responses in 16 of 20 patients.

Adaptimmune is developing NY-ESO-1— specific TCR-engineered T cells based on its proprietary SPEAR (specific peptide enhanced affinity receptor) T-cell platform. The results of an ongoing phase I/II study were presented at the 2017 American Society of Hematology (ASH) Annual Meeting. Following autologous stem cell transplant, 25 patients with advanced multiple myeloma were treated with NY-ESO-1 SPEAR T-cells. The objective response rate (ORR) at day 100 was 76%, 1-year progression- free survival (PFS) was 52%, median PFS was approximately 13 months, and median overall survival (OS) around 35 months. The most common adverse events (AEs) included diarrhea, nausea, anemia, decreased appetite, and thrombocytopenia.

Table 1. Selected Trials of TCR-Directed T-Cell Therapies in the United States

The use of next-generation genetic engineering technologies, such as CRISPR, is also being explored. The first clinical trial to use CRISPR in the United States involves TCR-engineered T cells designed to target NY-ESO-1. CRISPR will be used to delete the natural TCRs and PD-1 to help bypass some of the immunosuppressive mechanisms that can hinder ACT. The study is recruiting patients with multiple myeloma, melanoma, synovial sarcoma, or myxoid/round cell liposarcoma (NCT03399448).

The TCR is being manipulated for cancer therapy for a very different form of immunotherapy. Monoclonal antibodies targeting a variety of TAAs have revolutionized the treatment of numerous cancer types. The oncology research field has been seeking to expand on this success by investigating different antibody formats (

Among them are bispecific antibodies, which are engineered to combine single chain variable fragments (scFvs) from 2 different antibodies, allowing them to bind to 2 targets simultaneously. T-cell—targeted bispecific antibodies target a TAA with 1 scFv and the CD3 component of the TCR complex with the other. By binding to a TAA, the antibody can specifically target cancer cells, and binding to CD3 enables it to activate any T cells it encounters, redirecting their activity against the tumor without the need for their TCR to specifically recognize a TAA.

Simultaneous binding of tumor cell and T cell facilitates the formation of an immunological synapse, which results in T-cell activation, proliferation, and expansion at the site of the tumor and the destruction of the target cancer cell.

Although bispecific antibodies are limited to the recognition of cell surface TAAs, they are simpler and less time-consuming and laborintensive to produce than cell-based therapies. A variety of formats have been developed, often named after the proprietary technology platform used by the company developing them. The most advanced in clinical development are the bispecific T-cell engagers (BiTEs).

Blinatumomab, a BiTE targeting CD19 and CD3, gained FDA approval in 2014 for the treatment of patients with Philadelphia chromosome- negative, relapsed or refractory, precursor B-cell ALL.

 That accelerated approval was translated into full approval in July 2017, based on the results of the phase II ALCANTARA and phase III TOWER trials. In the former study, blinatumomab was compared with standard-of-care chemotherapy and found to nearly double median OS (7.7 vs 4 months; HR, 0.71; 

= .012). In the ALCANTARA trial, the efficacy of blinatumomab was evaluated in patients with Philadelphia chromosome-positive disease, and the efficacy it demonstrated in this population prompted the FDA to expand the indication into a broader range of patients.

In March, the FDA further expanded the indication to include postremission treatment of patients who have residual disease after their last chemotherapy treatment. This approval was based on data from the phase II BLAST study involving 86 patients in first or second hematologic complete remission 2 or more weeks after chemotherapy. Overall, undetectable minimal residual disease was achieved by 70 patients (81.4%; 95% CI, 71.6%, 89.0%). The median hematological relapse-free survival was 22.3 months.

Amgen, which manufactures blinatumomab, is continuing to develop the drug in ALL, diffuse large B-cell lymphoma, and other hematologic malignancies.

Table 2. T Cell-Targeting Bispecific Antibodies in Development

Growing Number of Antibodies in Development

MacroGenics, a big player in the development of bispecific antibodies, is working on a dual affinity retargeting (DART) antibody, flotetuzumab (MGD006), which targets CD123 and CD3. While BiTEs are composed of 2 scFvs fused to form a single polypeptide chain, DARTs are composed of 2 polypeptide chains linked by a disulfide bridge to help stabilize them.

Flotetuzumab was granted orphan drug designation for the treatment of acute myeloid leukemia (AML) in January 2017, and the results from an ongoing first-in-human, phase I trial in patients with AML and myelodysplastic syndrome were presented at the 2017 ASH Annual Meeting. The drug demonstrated acceptable tolerability and promising antitumor activity in the 14 patients evaluable for response treated at the threshold dose of 500 ng/kg/day and beyond who completed at least 1 cycle of therapy. The ORR was 43%, including complete remission or complete remission with incomplete hematologic response in 28% of patients.

REGN1979 is a bispecific antibody targeting CD20 and CD3 in development by Regeneron Pharmaceuticals. At the 2017 ASH meeting, the results of a phase I study of this drug in combination with the PD-1 inhibitor cemiplimab in patients with B-cell non-Hodgkin and Hodgkin lymphoma were reported. In the combination arm, 12 patients received 3 mg/kg of cemiplimab every 2 weeks for a minimum of 12 and a maximum of 24 doses, plus REGN1979 administered intravenously weekly for 11 doses, followed by every 2 weeks from week 13 for 11 additional doses. There was 1 partial response (PR), and 4 patients experienced stable disease.

Components of the T-cell receptor complex, which links antigen recognition with T-cell activity and effector function, are being exploited for several types of cancer immunotherapy.

Vol. 19/No. 9 | Oncology Live®

Persistence and the Quest for Innovation Guided a Radiotherapy Pioneer

Promising Umbralisib Combinations Tested in NHL Subtypes

5 Key Elements Needed to Achieve Success With the Oncology Care Model

The Looming Squeeze on Provider Revenues

Findings Clarify Picture for HER2-Positive Breast Cancer

Manipulating the T-Cell Receptor Yields Promising Immunotherapies

Patient Shortage for Cancer Trials Grows

What Can We Learn From "Extreme Survivors" of Breast Cancer?

All Is Not Well in the World of Academic Scientific Enterprise