	Washington University School of Medicine

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are the two most common hematologic malignancies of the myeloid lineage origin and both are more common in older patients. The median age of diagnosis for AML is around 67 years and has an estimated prevalence of 3.8 cases per 100,000. Unfortunately, less than half of AML patients are cured with current treatment approaches. The prognosis is particularly poor in older patients (≥60 years), in whom the success of achieving complete remission are significantly lower than younger patients and the long-term disease free-survival is often measured in single digits if patients are not eligible for stem cell transplantation. Furthermore, patients who are unable to achieve complete remission and or relapse after two or more chemotherapeutic regimens have extremely dismal outcomes, even with stem cell transplantation.

MDS is also more common in older patients and their long-term curative options are also limited if they are not eligible for stem cell transplantation. MDS patients without treatment often progress to acute myeloid leukemia. Hypomethylating agents, including azacytidine and decitabine, are the only class of medications that have demonstrated some clinical efficacy in these patients. However, patients with MDS who have failed and/or progressed while on hypomethylating agents have very limited treatment options.

Even with stem cell transplantation the outcomes are suboptimal in MDS patients with pretransplant high blast counts, underscoring an urgent need for developing more innovative treatment options for these patients.

Natural killer (NK) cells are innate immune lymphocytes important for host defense against pathogens and surveillance against malignant transformation. Early phase studies have demonstrated that allogeneic NK cells are a promising cellular therapy for leukemia. However, limited persistence and expansion of the adoptively transferred NK cells seen in previously reported studies remain some of the major limitations of the currently used strategies for NK cell—based immunotherapy protocols.

Recent work in the NK cell field has challenged their classification as members of the innate immune system, identifying memory-like properties of NK cells. This has included the identification of human cytokine-induced memory-like (CIML) NK cells by our group at Washington University School of Medicine, following preactivation with IL-12, IL-15, and IL-18. Human CIML NK cells exhibit enhanced cytokine and cytotoxic responses against myeloid leukemia target cells and they retain this enhanced functionality following transfer into immunodeficient NOD-SCID-gc-/- mice. Based on their enhanced antileukemia responses and ability to proliferate and expand after adoptive transfer, CIML NK cells are an attractive option to explore in relapsed/refractory AML and in MDS patients who have failed and/or progressed on hypomethylating agents.

We are currently enrolling patients on a firstin- human phase I study using CIML NK cells for advanced MDS and AML patients.

Eligibility: Patients (≥ 18 years) with one of the following diagnosis:

Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR.

High-risk AML in complete remission (CR) and has either refused hematopoietic stem cell transplantation or is currently not eligible for hematopoietic stem cell transplantation or for whom hematopoietic stem cell transplantation is being reserved for later relapse.

 MDS with excess blasts (>5%) and failed/progressed with the hypomethylating therapy.

 It is a standard 3(+3) dose escalation design and includes 3 dose levels (0.5x106/kg, 1x106/kg, and all available CIML NK cells). Patients receive haploidentical donor CIML NK cells on day 0 after a nonmyeloblative regimen. CIML NK cells are generated from the peripheral blood NK cells donated by an HLA-haploidentical (“half matched”) related family member using a standard non-mobilized (without any growth factor or G-CSF) apheresis session. Peripheral blood NK cells are processed and activated with a cocktail of cytokines (IL-12, IL-15 and IL-18) over 12-16 hours to generate CIML NK cells at the Biologic Therapy Core (BTC) of the Siteman Cancer Center. Treatment schema is shown in the 

Adoptively transferred CIML NK cells are tracked using HLA specific antibodies by flow cytometry. Patients are closely monitored for any adverse events and also undergo bone marrow biopsy at days 14 and 28 after their CIML NK cell infusion to document disease response. Patients who are able to achieve remission with CIML NK cells can proceed to a stem cell transplant and therefore, this treatment can be used as a bridge to transplant in eligible patients.

We have seen some encouraging results in the first few patients treated on this study. If found to be safe and with an efficacy signal in our current ongoing phase I study, we intend to initiate a larger phase II study in the near future. Efforts are also on to expand their usage to other hematologic malignancies, including multiple myeloma and lymphoma either alone or in combination with other novel immunotherapy approaches.

Further information about this novel protocol can be found at the Clinicaltrials.gov (Identifier: NCT01898783). Physicians who would like to potentially consider this study for their patients with AML or MDS can contact me at rromee@dom.wustl.edu or call my office number: (314)-454-8333. 

Articles

Acute myeloid leukemia and myelodysplastic
syndromes are the two
most common hematologic malignancies
of the myeloid lineage origin and both are more
common in older patients.

Memory-Like Natural Killer Cells for Patients With Advanced AML and MDS

Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

John Theurer Cancer Center at Hackensack University Medical Center

No one would deny that cancer care and healthcare at large are at a crossroads and need a change. Sky-high medication prices are emerging as a political issue. As I have discussed in previous columns, some of the novel cancer therapies are truly transformative and might replace chemotherapy in the future, though they have to be taken for years (until progression), while costing patients up to several thousands dollars a month. On the other hand, most approved drugs only work in a fraction of patients, with up to 30% to 70% of patients who 

benefit from them. This has huge implications for patients’ lives first, but also in terms of cost. Meanwhile, the biotech field continues with more promising new tools, drugs, and speculation. Lots—if not most&mdash;of these novel therapies result from a better understanding of cancer cell biology, which has also shed light on the enormous molecular diversity of cancer.

Personalized therapy, renamed precision or precise medicine (PM), has emerged as the answer to help improve patients outcomes. Thanks to high throughput technology, including genomic testing of each tumor, and each patient’s inherited DNA— along with proteomics in the future&mdash;oncologists will be able to tailor regimens for each case.

The field of emerging liquid biopsies will allow us to monitor patients’ responses in vivo and detect disease and/or relapse earlier. Having the ability to adjust therapy to a given patient is not new and is already being used in many ways including in oncology. For decades, detection of ER (estrogen receptors) and/ or PR (progesterone receptors) in breast cancer served as basis for hormone therapy and prognostic evaluation. Nowadays, a growing panel of defined mutations helps choose a TKI (tyrosine kinase inhibitor) in CML or in lung cancer, for example.

On the other hand, critics argue PM has become just a “buzzword” and we should keep with the statue quo and continue the current drug development paradigm. To their point, two recent papers reporting on “picking a treatment” based on molecular features were rather disappointing. In the first one, the BASKET trial (Lopez- Chavez A, et al. 

 2015;33[9]:1000-1007) in lung cancer, the authors concluded that their trial was not feasible for many of the study arms that had patients with rare mutations. The second one— the SHIVA trial (Le Tourneau C, et al. 

. 2015;16[13]:1324- 1334.)—looked at 741 patients with advanced refractory cancer, who were given either a molecular targeted agent outside the known approved indication (based on molecular profiling) versus investigators’ choice and showed no benefit in outcome.

Skeptics claim PM has not delivered overall and point to a tendency of both public and care providers to imbue emerging innovation (not only DNA sequencing but also other new technologies) with almost mystical powers. The only way to escape the expectation/disillusionment cycle is for genomics and PM to demonstrate a tangible impact. This will happen when sequencing is embraced not because it’s interesting or “edgy,” but because it’s so obviously useful.

When enough patients will be sequenced, more reliable signatures and patterns will likely emerge (as opposed to statistical noise). Biomarker-based trials need to be embraced and supported both by pharma but also by regulatory authorities. Too often, such efforts toward correlative science in early trials are either simply ignored, or not supported based on extra cost or risk (additional procedures) and too frequently hence recommended as optional by local IRBs. Finally, mutation-based trials are frequently slow in turn around leading to difficult enrollment and/or biased (easiest cases) populations.

That being said, the cost of cancer care in the United States is estimated at over $200 billion a year and will continue to rise as our population expands and lives longer (with a projected expected increase of over 40% in cancer incidence in the next 30 years). Global oncology statistics also show that drug-related expenses surpassed $100 billion in 2014. Those are huge numbers, without even accounting for the hidden cost of lost productive years, in addition to the emotional toll on friends and family.

Because a high proportion of these costs are incurred at the end of life and/or have no real impact on outcome, some believe that palliative care with hospice should be an option offered much earlier for many patients…This is debatable for several reasons, including the impact we see with some novel therapies at this point, particularly in immuno-oncology.

The problem is, we are not there yet in PM and more education and changes of behavior are needed for all stakeholders. This sounds simple but is definitely not easy. Even in cases with strong evidence-based medicine, changes occur slowly for multiple reasons including human nature among other things.

Paying for a test that in lung or breast cancer might spare a patient chemotherapy is obvious but is still not done routinely or in some cases, it’s done but not subsequently used. Current pricing of molecular testing is still very high (several thousands to have one or maybe two “actionable” items), but this will go down as competition increases and testing is used more frequently. However, it is likely too simplistic to think—as illustrated by the two papers cited above&mdash;that one mutation will really help in practice given the diversity and complexity of cancer cells.

The often breathless excitement around the promise of PM has generated a pointed response from skeptics, who appropriately ask whether the science has been oversold. I would argue that the optimal treatment of cancer should and hopefully will become, like in HIV, a rationale combination of targeted agents based on “actionable” profiles of tumors. This is obviously every oncologist’s dream and I think that only then will we make true progress. This also implies dramatic changes in drug development including codevelopment of drugs early on.

PM is and will be good for everyone. It already can and will help cancer patients by sparing them the toxicity—and time&mdash;of trying ineffective drugs. It will cost much more before it costs less. However, the extra short-term cost should be put in perspective with the huge waste seen in oncology, particularly later in the disease course with no impact on outcome. The rapidly changing landscape in the pipeline calls for new ways to develop trials and speed up approval process, which in itself might reduce drugs costs. The integration of big data in this revolution is essential, although to not fall again into the hype, digital data needs to be meaningful and reflect the patterns seen in the real world. It also needs to engage all stakeholders, including patients that need to be part of monitoring their clinical benefit (which will also help compliance for mostly oral drugs at this point).

Our goal should be to use PM as a way to deliver value-based care. This critical endeavor needs to be embraced by everyone in oncology, while impassionate PM champions keep the fire going…

Our goal should be to use precision medicine as a way to deliver value-based
care.

Precision Medicine Carries Significant Challenges but Will (Eventually) Lower Cancer Care Costs and Is the Way to Go (Precisely)

Over the last month or so, the immune checkpoint blockade revolution in oncology has officially hit a fever pitch. From regulatory approvals and milestones to the release of the latest positive data, success with checkpoint agents continues its rapid advance across tumor types to nearly every corner of cancer care.

FDA recently approved the PD-1 inhibitor pembrolizumab

 (Keytruda) for patients with pretreated, PD-L1—positive advanced non–small cell lung cancer. The regulatory agency also 

expanded the NSCLC approval of the anti—PD-1 agent nivolumab

 (Opdivo), adding a nonsquamous indication to the previously authorized use for squamous patients. Also in lung cancer, data presented at the 2015 World Conference on Lung Cancer showed that adding the PD-L1 inhibitor atezolizumab to chemotherapy improved responses in the frontline setting for patients with metastatic NSCLC. 

 has also shown efficacy as a single-agent in patients with pretreated advanced NSCLC, according to results from two pivotal phase II studies presented at the 2015 European Cancer Congress (ECC).

Combining checkpoint agents is also a key strategy going forward, with a r

egimen of nivolumab plus the CTLA-4 inhibitor ipilimumab

 (Yervoy) demonstrating frontline activity in advanced NSCLC, according to early data presented at the World Lung meeting. The 

 the combination of nivolumab and ipilimumab as a treatment for patients with 

 wild-type unresectable or metastatic melanoma. There have also been significant recent developments with checkpoint agents in the genitourinary setting. Nivolumab received an F

 for the treatment of patients with advanced renal cell carcinoma. Studies presented at the 2015 ECC showed positive clinical activity for atezolizumab and another anti—PDL1 agent, avelumab, in patients with metastatic urothelial carcinoma. The checkpoint juggernaut is also starting to reach blood cancers. Although the research is early, there is a potentially significant role for immune checkpoint inhibition in the treatment of lymphoma, according to a discussion at the recent 2015 Society of Hematologic Oncology (SOHO) annual meeting.

It’s important to note that there is still much work to be done on the immuno-oncology front—reliable biomarkers and companion diagnostics are absolutely essential to ensuring that the greatest number of patients are receiving the greatest possible benefit from these agents. Payer issues will also have to be resolved, given the high cost of these drugs, especially when used in combination regimens.

However, even with these challenges, there is no denying that the immune checkpoint blockade revolution has changed the course of oncology. The miraculous advances with these agents in the past 5-plus years alone is a true testament to the passion and innovative spirit you bring to the lab and/ or clinic. We at 

 can’t wait to see what frontiers the great immuno-oncology journey takes us to next.

Over the last month or so, the immune checkpoint blockade revolution
in oncology has officially hit a fever pitch.

October 2015 | Oncology & Biotech News

Memory-Like Natural Killer Cells for Patients With Advanced AML and MDS

Precision Medicine Carries Significant Challenges but Will (Eventually) Lower Cancer Care Costs and Is the Way to Go (Precisely)

Checkpoints at Every Turn