Louis M. Staudt, MD, PhD, has an eye for patterns. 

As director of the National Cancer Institute’s Center for Cancer Genomics, sometimes the patterns that absorb his mind are gene expression profiles that explain why tumors act the way they do. Sometimes, though, the lifelong amateur pianist is transfixed by the patterns in the music of the great composers. 

“If you’re playing a Bach toccata and you’ve played a lot of Bach toccatas before, even if you’re playing [this one] for the first time, you pretty much know what the next group of notes might be,” Staudt said. 

In his 4 decades as a scientist, Staudt has made key insights into the genomics of lymphoma and reshaped the way clinicians risk-stratify and treat patients. Many of his greatest discoveries have started with his ability to see the big picture from a small sample.

“Lou is pretty unique in his ability to take a modicum of data that’s not very large and make the observation from the data that is the most salient, most important thing,” said Ash Alizadeh, MD, PhD, a former student and longtime collaborator of Staudt’s.

If his ability to identify patterns has played a major role in Staudt’s career, that career was only possible because of his willingness to deviate from what appeared to be his logical next step after college.

Staudt grew up in Michigan, where his mother was a nurse who ran the operating room at the Children’s Hospital of Michigan and his father was a physician for the Chrysler Corporation. 

“He would do an occasional house call with Lee Iacocca,” Staudt recalled. 

As a child, it was obvious that Staudt inherited some of his parents’ interests. His love for math and science was evident from an early age. “I’m not ashamed to say I was a nerd,” he said. 

He was also into music. When he got to Harvard University, he likes to say, he “majored in Glee Club.” In truth, he majored in biochemistry, although his role as president of the famed choral group took up much of his time and his fellow singers comprised much of his social circle, he said.

After college, though, Staudt faced a choice. He wanted to go to graduate school, but he was not sure whether to follow his parents’ path and enroll in medical school or pursue a career in the laboratory. His parents, not surprisingly, had a strong preference. “They were like, ‘You’ve definitely got to go to medical school,’ ” he said, remembering that his dry creaction was, “ ‘Yeah, no kidding!’ ”

Staudt makes a point to then-Vice President Joseph R. Biden following the announcement of the NCI Genomic Data Commons project in 2016.

Also, during his time at Harvard, Staudt had been introduced to the rapidly changing field of immunology. He was hooked. “Science is a little bit like an addiction,” he said. “When you get a good result, you just crave the next good result.” 

Still, Staudt said, since he remained torn between jumping fully into science or following the path of his parents, he decided to “hedge” by enrolling in a joint MD/PhD program at the University of Pennsylvania. Walter Gerhard, MD, Staudt’s graduate mentor, had no such ambiguity about Staudt’s future. 

“I always thought he would remain 100% in science,” he said.

At Penn, Staudt began working on the influenza virus, looking at ways that monoclonal antibodies could neutralize it. “That was the basis of my thesis, but just almost by luck, I stumbled across what turned out to be an important aspect of the diversification of immune responses,” he said.

What Staudt “stumbled upon” was somatic hypermutation, the rapid mutation of immunoglobulin genes that helps explain the diversity of responses to the influenza virus.

Gerhard said the discovery of somatic hypermutation showed “that the antibody response of mice to a hemagglutinin molecule of influenza virus was very diverse. Different individuals responded in quite different ways.”

Gerhard said Staudt was successful because he was extremely organized. Well, mostly. “You wouldn’t have thought that if you would have seen his backpack, which was kind of full of loose papers,” he said of his star pupil.

Looking back, Gerhard said that early influenza research showed a skill set that would prove important in some of Staudt’s later work, analyzing genes associated with diffuse large B-cell lymphoma (DLBCL).

“I think what he did with tumor research helped him in his subsequent work,” Gerhard said. “To do that work without making a mess required a lot of organization, and he was very good at that.”

After graduate school, Staudt did a postdoctoral fellowship with Gerhard at the Wistar Institute, in Philadelphia, and then an internship in internal medicine. He credits the internship with helping him to understand the practical considerations of a clinician, which in turn has helped him design feasible clinical trials.

Staudt then joined the Whitehead Institute, working in the laboratory of David Baltimore, PhD, where the focus was on trying to figure out which transcription factors were particularly important in controlling the transcription of genes related to lymphoma. Most of the factors the researchers were examining were commonly found in other types of cells. Then, Staudt observed a transcription factor called Oct-2 seemed to be found only in lymphoid cells.

“That seemed to also open up the possibility that a set of regulatory factors is specific for a stage of B-cell differentiation, and that [these factors] were why the B cell has the properties that it does,” he said.

Staudt was among the first to recognize the potential of genomic analysis to identify new cancer types, therapeutic targets, and biomarkers.

It would take 3 more years to identify the gene that was encoding the transcription factor, thereby confirming that there was a lymphoid-specific expression pattern. That work led Staudt to the National Institutes of Health—the National Cancer Institute, specifically, which he joined in 1988. There, Staudt continued his quest to find genes that were expressed only in lymphoma cells.

“What I really yearned for was a way to study all the genes, every last one in the genome,” he said.

Back then, that level of analysis was not on the radar of most people in the field. Stanford University’s Patrick O. Brown, MD, PhD, however, was among the relatively few investigators in the world who shared Staudt’s interest in unlocking the genome. (Brown, incidentally, went on to become the founder and CEO of Impossible Foods, a leading producer of plant-based meat products.)

Brown had developed the DNA microarray, a way to look at the transcription levels of thousands of genes at the same time. A friend of Staudt’s came back from a visit to Stanford and told him about the invention. 

“So the very next day, I cold-called Pat—I had never met him before—and explained my interest,” Staudt said. “And Pat, being the really open, inquisitive guy that he is, just said, ‘Great! Let’s do something together.’ ” 

Staudt and his team discovered that DLBCL, thought to be 1 disease, was actually 7 distinct maladies.

Alizadeh, now a professor at Stanford, worked with Staudt and Brown to develop what they termed the “Lymphochip,” a DNA microarray heavily enriched for genes that were expressed in normal and malignant B cells. Alizadeh noted that, at the time, the human genome had not yet been fully sequenced. 

“We had bets about how many genes were in the genome,” Alizadeh said. “Most people guessed around 100,000. The first lympho-chip had 6000 genes, so investigators assumed they had about 5% or 6% of the genome. It ended up being about a third of the genome.” 

The work they were doing in Staudt’s lab was painstaking and time-consuming, requiring great accuracy, diligence, and persistence. Alizadeh said he does not think Staudt and his other colleagues realized how big of a project they were embarking upon.

“But I also think that he was really looking toward a new chapter, and a new kind of science,” Alizadeh said. 

When the team began to study DLBCL tumors using their lympho-chip, they began to see distinct expression patterns. “But it wasn’t just that we found a pattern,” Staudt said. “It was that we found a pattern that related each of the tumors to a different stage of normal B-cell differentiation.” 

This was the discovery that would lead to an important realization: What had been thought of as a single disease, DLBCL, was actually 2 molecularly distinct diseases, germinal center B-cell– like DLBCL and activated B-cell–like DLBCL. The finding helped investigators realize that the 2 subtypes responded differently to chemotherapy. Eventually, Staudt and his colleagues identified 7 distinct DLBCL subtypes.

Staudt was president of Harvard’s Glee Club and says he is a good amateur piano player. Performance anxiety killed any chance for a career in music.

“That has led to therapies that work better in one [subtype] than in the other, and to the whole idea of precision medicine,” Staudt said.

Staudt would go on to demonstrate that survival following chemotherapy among patients with DLBCL correlated with molecular features. These findings had applications across other malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and follicular lymphoma.

Staudt has continued in his work, in terms of both expanding knowledge of the subtypes of DLBCL and helping to develop therapies. His team discovered the nuclear factor (NF)- κβ pathway as a therapeutic target, and showed that its activation depends on chronic activity of B-cell receptors in lymphomas. He discovered that drugs like ibrutinib (Imbruvica) that inhibit B-cell receptor-dependent NFκβ signaling were killed malignant B-cell lymphoma cells. Ibrutinib is currently approved for use in patients with MCL, CLL, Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft-vs-host disease.

Staudt outside the world-famous Louvre Museum in Paris, France

Alizadeh said Staudt helped transform cancer medicine because he visualized the power of genomic analysis. While genetic characteristics like HER2 or EGFR expression were already being used, Staudt realized that a wider lens could magnify the insights.

“To [see] that extending this to the genome [would] help build a taxonomy of cancer and discover new cancer types—that was visionary,” Alizadeh said.

Staudt lives with his wife, the poet and scholar Kathleen Henderson Staudt, PhD, outside Washington, DC. They have 2 grown children, a son who trained as a pediatric cardiologist and is now working on translational research, and a daughter who is an attorney who has fought to reform bail laws in Illinois.

Staudt said that his work at NCI consumes most of his time, but that he loves to read in his rare free moments. This summer, he was reading the book 

Behave: The Biology of Humans at our Best and Worst

 by Stanford neuroscientist Robert Sapolsky, PhD.

“He goes right down to the basic science of neurotransmitters, to which parts of the brain do what,” he said. But, he added, Sapolsky also zooms out to explain the connection between that basic science and the behaviors that impact society and the planet, translating the basic science to reveal its real-world impact.

Staudt’s discovery that survival in DLBCL correlated with certain molecular features revolutionized treatment across multiple other malignancies.

In fact, much of what Staudt reads is nonfiction. He likes biographies of great individuals, particularly of great scientists, he said. “The last fiction book I think I read was Dune,” Staudt said. “I read it because I wanted to see the movie.”

Staudt also makes sure music is a part of his everyday rhythm. He plays the piano daily and considers himself a “very good amateur.” However, don’t expect a Staudt recital any time soon. These days, he simply plays for his own enjoyment. “When I was younger, I did try to give recitals,” he said. “I would routinely forget things and freeze, and it was really ugly.”

Although Staudt has built a career out of finding patterns in science and math, he said that one thing he loves about music is how it transcends the mathematics of rhythms and notes.

“It’s also this vaguer, important emotional content that comes in ways that you can’t really specify,” he said. “That really is a big part of why you play music. It’s not just another form of mathematics.”

Indeed, Staudt said part of his work as a scientist is also about the interplay between the patterns and the broader picture. He recalled being nervous when he was about to publish his first paper, wondering if he had studied enough cases to back up his findings.

“I knew full well that even though it was statistically significant, the thing could fall flat on its face,” he said. “But my approach has always been, let’s just wrestle this to the ground. Let’s just keep on seeing whether it’s true.”

Articles

Driven by his twin passions for music and science, Louis M. Staudt, MD, PhD, has made a career out of reading between the notes.

For Staudt, a Keen Eye Sparks Opportunities to Dig Deeper

Five years since the first FDA approval of CAR T-cell therapy in relapsed/refractory lymphoma, there is still much to learn about how to optimize its use.

 “It’s far better than autologous stem cell transplantation,” said Sattva S. Neelapu, MD, professor and deputy department chair, Department of Lymphoma/Myeloma, of The University of Texas MD Anderson Cancer Center in Houston. “It’s offering hope for patients who previously did not have any other options and had a median survival of [approximately] 6 months.”

However, Neelapu said the therapy has not reached its full potential, neither in terms of the underlying technology nor its uptake among eligible patients. “There’s still a lot of room for improvement,” he said.

Neelapu will discuss the use of CAR T-cell therapies in lymphoma during a presentation on September 30, 2022, at 1:02 pm during the 

Meeting of the Society of Hematologic Oncology (SOHO 2022) in Houston, Texas. His talk, “CAR-T in Lymphoma Future Directions: Targets, Resistance, and Persistence,” will include some of the latest CAR T–related trial results, as well as a discussion of how best to optimize cell therapy.

Growing Armamentarium of CD19-Targeted Therapies

Axicabtagene ciloleucel (Yescarta) was the first CAR T-cell therapy approved for lymphoma but was quickly followed by similar therapies.

 “Currently, there are 4 different CAR products that have been FDA approved for lymphoma,” Neelapu said. “All of them target CD19.”

Three of those products are approved to treat large B-cell lymphoma. In addition to axicabtagene ciloleucel (axi-cel), the FDA also approved lisocabtagene maraleucel (Breyanzi) and tisagenlecleucel (Kymriah) for certain patients with B-cell lymphoma,

 as well as brexucabtagene autoleucel (Tecartus) for relapsed or refractory mantle cell lymphoma.

 In addition, axi-cel and tisagenlecleucel are also approved for follicular lymphoma. Neelapu said those approvals mean that a large number of patients are eligible for CAR T-cell therapy, but the existing data suggest the therapy will often be ineffective over the long term in the majority of patients. Only approximately 4 in 10 patients achieve long-term remission with CAR T therapies, Neelapu said.

What makes matters even more perplexing, he said, is that the treatment’s long-term remission rate remains at approximately 40%, even when it is moved up into the second line of therapy rather than the third.

 “We generally expect that when we move to earlier lines, we see a better outcome,” Neelapu said. “But that was not the case.”

Although the results still outperformed the standard-of-care treatment with salvage chemotherapy followed by autologous stem cell transplantation, Neelapu said there is scope for further enhancement. Moreover, despite the fact that CAR T-cell therapies have been available for 5 years, their uptake in the commercial setting has remained relatively low.

Neelapu estimates there are perhaps 10,000 individuals with B-cell lymphoma in the United States who would qualify for CAR T-cell therapy each year. However, he estimates that only approximately 20% to 25% of those who are eligible are getting the treatment. There are multiple possible reasons for the relatively low eligibility-to-uptake ratio—one being access. Neelapu said there are approximately 120 centers in the US that can provide the therapy, which averages to just 2 or 3 centers per state.

“It’s not nearly enough,” he said. “It requires patients to travel to another center and stay locally for a period of at least 5 to 6 weeks—along with the caregivers—to be able to get the treatment, so it is not practical for everyone.”

In addition, the fact that the current CAR T-cell products are autologous means each product has to be custom made for a specific patient from the patient’s own T cells, which increases both the cost of the therapy and the wait time. In a best case scenario, Neelapu said it can take 5 weeks for a patient to receive the product from the time a need has been identified.

“So [although] the existing products appear to be probably the most effective [therapies] available for large B-cell lymphoma, there are limitations and various things can be done to overcome those limitations,” he said. “That’s where I think the future is.”

In his SOHO 2022 presentation, Neelapu will delve into those efforts. One focus, he said, is overcoming mechanisms of resistance among the roughly 60% of patients who relapse after CAR T-cell therapy. Investigators are working on ways to design new CAR T-cell products that will be more effective in patients, with resistance to CD19-targeting products. Those strategies include targeting different antigens or changing the way the product is designed and manufactured.

“From a clinical development standpoint, post-CD19 CAR failures are the biggest unmet clinical need in large B-cell lymphoma,” he said. “In these patients, none of the existing treatments really work well.”

Neelapu said one issue is that approximately 30% of patients with diffuse large B-cell lymphoma are CD19 negative following treatment with axi-cel.

 “[This] means that if we target different antigens, [we] could potentially overcome that mechanism of resistance,” he said. “We are fortunate in B-cell lymphomas, because there are so many targets we can choose from.”

One of the most interesting potential targets is CD22, Neelapu said. A phase 1 trial (NCT04088890) published in 2021 showed that patients who were refractory to CD19 CAR T-cell therapy and then were treated with a new CD22-targeted product experienced improvement.

“[Investigators] found a very high complete response rate, and a lot of them appear to be durable,” Neelapu said. “This is probably the most promising evidence that targeting a different molecule can be effective in the clinic in large B-cell lymphoma.” However, he also added that it’s not clear whether targeting CD22 will be more effective than other potential targets, such as CD20, CD79A, or CD79B. Those questions will require more research.

In the meantime, Neelapu said it may be wrong to think about the next step as choosing the best single target. “In the long term, we’d like to target multiple antigens at the same time,” he said. “And there are bispecific CARs and trispecific CARs that are in clinical trials now.”

Another suspected driver of resistance is suboptimal numbers of fit T-cells. Neelapu said experimental use of CAR T-cell therapies in a first-line setting led to the discovery that products derived from patients in an earlier line of therapy seem to lead to better results. “When we compared CAR T products in patients who were treated in the first line vs the third line, we found that the quality of the product was much better in terms of the T-cell phenotype and functionality,” he said.

In his presentation, Neelapu plans to review the ZUMA-12 trial (NCT03761056), a phase 2 trial that looked at axi-cel as part of first-line therapy in high-risk patients with large B-cell lymphoma. In that study, high-risk patients underwent 2 cycles of systemic chemotherapy. Patients who still had residual disease on a PET scan were then given an infusion of axi-cel. The study achieved an 89% objective response rate among the 40 patients treated. The response also appears to be durable; at 1 year, approximately three-quarters of patients were still in remission.

 “[This] is a lot higher than the 40% seen in second- and third-line settings,” he said.

Another strategy to improve the quality of CAR T-cell therapies is to optimize and accelerate the manufacturing of the therapies. For instance, Novartis has created a platform known as T-Charge, which dramatically speeds up the manufacturing process. YTB323 is a CD19-targeted CAR T product that uses the same design as tisagenlecleucel, but it is manufactured using a new, faster method.

“The production of CAR T cells used to require culturing the cells for [approximately] 10 to 14 days in the lab, but now with the T-Charge platform, it has been shortened to 2 days,” Neelapu said. “When they did that, they found that the function and the phenotype of the T cells [was] much better.”

A third apparent mechanism of resistance to CD19 CAR T-cell therapy is intrinsic tumor resistance. “[Essentially, for various reasons], the tumor cells resist CAR T–mediated killing,” he said.

Neelapu said several potential mechanisms for intrinsic resistance have already been identified, but strategies to overcome intrinsic resistance are still in the early phases of development. He expects to see significant progress in this area in the coming years. “We will probably uncover a lot more resistance mechanisms than what we currently know,” he said.

If 1 major focus of CAR T development is centered around evading resistance, Neelapu said another key strategy is finding ways to use allogeneic cells instead of autologous cells to derive therapies. Using allogeneic cells can allow something like an “off-the-shelf” approach to CAR T-cell therapy, rather than the time-consuming process of making patient-specific doses. It would also allow manufacturers to make many more doses from a single donor and would likely significantly reduce the cost of the therapy. But there’s 1 key problem, Neelapu said. “The main hurdle we are seeing right now in some of these early studies is that these cells don’t persist as long in the body,” he said.

Although autologous CAR T cells can persist for years in the body, the current allogeneic products do not come close to that level of durability. “With allogeneic CAR T products, most of the time they persist in the body for only 1 or 2 months, because once the host immune system recovers in a patient, they reject these allogeneic cells,” Neelapu said.

The ALPHA-2 study (NCT04416984) of ALLO-501A (Allogene Therapeutics, Inc) is 1 attempt to solve that problem. “One approach taken by the Allogene product is that they knock out this molecule called CD52, which allows them to give a better conditioning regimen with anti-CD52 antibody on top of cyclophosphamide and fludarabine to induce this prolonged lymphodepletion in the patient,” he said. “That way, the rejection may be delayed.”

Neelapu said many other approaches are currently being investigated or are soon to be the subjects of clinical trials. He thinks allogeneic therapies will likely win out over the long term. “They will likely be the future for cell therapies,” he said.

For community oncologists, Neelapu said chemotherapy remains the standard choice for first-line therapy for large B-cell lymphoma, as it cures 60% to 65% of patients. In the second-line setting CAR T therapy is now the standard of care. “If we ask the question, as a second line: What is the treatment that has the highest chance of achieving a cure in these patients? That’s CAR T,” he said.

As a practical matter, Neelapu said it is important for community oncologists to refer patients to a CAR T therapy center early, as there is some evidence that multiple prior therapies can diminish the effectiveness of autologous CAR T-cell products. “Early referral by the community oncologist at first relapse is key to achieve an optimal outcome and the best chance of cure,” he said.

In situations where economic or other barriers make it difficult for a patient to get treatment at a CAR T center, Neelapu said bispecific antibody therapies may soon be available. Such treatments could be a good bridging option, because unlike chemotherapy, they do not affect T-cell numbers or functions.

SOHO and the Return of In-Person Meetings

Reflecting on SOHO 2022 and the return to a fully in-person meetings, Neelapu said the virtual format necessitated by the COVID-19 pandemic had certain advantages. “I think Zoom has, in some ways, encouraged more people to attend,” he said. “And if it’s a live virtual presentation, we see a lot more people asking questions.”

However, he said he’s looking forward to something Zoom cannot provide. “With an in-person meeting, what’s appealing is to talk offline with colleagues and investigators from academia and industry,” he said. “[This] can generate a lot of interesting discussions, new ideas, and collaborations—that’s missing in a virtual meeting.”

Kite’s Yescarta (axicabtagene ciloleucel) becomes first CAR T therapy approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. News release. Gilead Sciences, Inc; October 18, 2017. Accessed August 21, 2022. https://bit.ly/3KfFvLi

FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. News release. FDA; April 1, 2022. Accessed August 30, 2022. https://bit.ly/3wHlnME

Approved cellular and gene therapy products. FDA. August 17, 2022. Accessed August 30, 2022. https://bit.ly/2HhGlbl

Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) significantly improves outcomes, showing superiority over 20-year standard of care in second-line relapsed or refractory large B-cell lymphoma based on TRANSFORM study results. News release. Bristol Myers Squibb; December 11, 2021. Accessed August 21, 2022. https://bit.ly/3CsOPK3 

Kymriah (tisagenlecleucel), first-in-class CAR-T therapy from Novartis, receives second FDA approval to treat appropriate r/r patients with large B-cell lymphoma. News release. Novartis; May 1, 2018. Accessed August 21, 2022. https://bit.ly/3QH1QUx

U.S. FDA approves Kite’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News release. Gilead Sciences, Inc; July 24, 2020. Accessed August 21, 2022. https://bit.ly/3PRDpT8

Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. 

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Spiegel JY, Dahiya S, Jain MD, et al. Outcomes of patients with large B-cell lymphoma progressing after axicabtagene ciloleucel therapy. 

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Frank MJ, Baird JH, Patel S, et al. CD22-CAR T-cell therapy mediates high durable remission rates in adults with large B-cell lymphoma who have relapsed after CD19-CAR T-cell therapy. 

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Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. 

Flinn IW, Jaeger U, Shah NN, et al. A first-in-human study of YTB323, a novel, autologous CD19-directed CAR-T cell therapy manufactured using the novel T-Charge platform, for the treatment of patients (pts) with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). 

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Five years since the first FDA approval of CAR T-cell therapy in relapsed/refractory lymphoma, there is still much to learn about how to optimize its use, according to Sattva S. Neelapu, MD.

Investigators Set Sights on Optimizing CAR T-Cell Therapy in Lymphoma

Walter J. Curran Jr, MD, started a new job this year working for an Australia-based oncology services provider, so it’s no surprise that he spent the summer with his mind and his device screens tethered to the other side of the world.

Then again, those who know Curran realize that his new job wasn’t the only thing drawing his attention eastward. He was also glued to the 2020 summer Olympics in Tokyo. During an early July interview, Curran explained that he had just finished “watching as much of the US Olympic track and field trials” as he could. A month later, when asked if the same was true of the track and field events at the Olympics, he replied: “Yes, indeed.”

Curran, who turned 70 in April, is not just a spectator when it comes to running.

“I ran the Atlanta Pride 5K race a week ago here in the rain, and then I’m going to run the masters mile in the Penn Relays up in Philadelphia in a couple weeks,” he said.

Curran has run all his life, dating to his days growing up on the North Shore of Boston, Massachusetts. “I had a high school track coach who influenced a whole generation of people I grew up with in a very positive way,” he said.

Later, Curran would become a track coach himself. And even after he became a physician and began his rapid rise to the top of the field of radiation oncology, he always found time to run.

“I don’t know any better,” he said. “I still run.”

In January, Curran stepped down after more than a decade as executive director of Winship Cancer Institute of Emory University, taking a job as global chief medical officer at GenesisCare, an oncology-care network with more than 380 locations around the world. At Emory, Curran also chaired the Department of Radiation Oncology. In addition, he served as a founding group chairman of NRG Oncology, a National Cancer Institute–funded clinical trial cooperative group.

Curran is known for his wide-ranging expertise and interdisciplinary approach, particularly in the care and research focused on patients with lung cancer or brain tumors. However, the start of his decades-long career in medicine was anything but typical.

“In my senior yearbook in high school, I said I wanted to be an engineer,” he said. “And I think that had to do with growing up in the technology belt around Boston.”

Curran’s goals had changed by the time he met with his undergraduate adviser at Dartmouth College. He told the adviser that he wanted to teach school, coach track, and then become a physician. No one was more surprised that he was going into medicine than Curran himself.

“I don’t think I ever thought about that before that moment,” he recalled. “But those are the words that came out of my mouth, and so I stuck to it.”

Curran taught for 5 years, including 3 years teaching middle school science at a newly integrated public school in rural Georgia. In addition to teaching, he coached track, with one of his athletes tying Jesse Owens’ record in the 100-yard dash. Because that student was in special education, running track in college was not an option for him. Instead, Curran arranged for him to join the US Marine Corps, where he was able to run on their track team.

“[Teaching] is the hardest work I ever did, especially my first year, but it also requires a sense of comfort with yourself and poise that is really probably more significant than at any job I ever had,” Curran said.

Still, he felt his true calling was medicine, so he enrolled at the Medical College of Georgia. He zeroed in on radiation oncology during a rotation at Harvard Medical School’s Joint Center for Radiation Therapy.

“What grabbed me was the tremendous diversity of patients…the fact that radiation oncologists really had extraordinary breadth and depth of knowledge as applied to patients— whether they were pediatric patients or adults with brain tumors, lung cancer, breast cancer, or [gastrointestinal] cancers,” he said. “And there was really an inspiring group of faculty and residents in that program.”

Curran completed his residency at the University of Pennsylvania radiation oncology program before joining the faculty at Fox Chase Cancer Center in Philadelphia. He was then recruited to chair the Department of Radiation Oncology at Philadelphia’s Thomas Jefferson University Hospital.

Ben W. Corn, MD, who was vice-chair under Curran at Thomas Jefferson in the mid-1990s, says Curran stood out for his collaborative approach to colleagues.

“Some people in academic medicine just keep to themselves, but that was never his way,” said Corn, now a professor of oncology at Hebrew University of Jerusalem. “The greatest Wally Curran contribution is just his commitment to cooperation.”

Despite working in a field where publication bylines and individual credit are the currency for advancement, Curran was constantly seeking to partner with others. “He’s got drive,” Corn added. “But for Wally, it’s overwhelmingly about the cooperative opportunities.”

True to form, Curran said that one of the things he is most proud of is his ability to build successful teams. “Not my personal achievements,” he said, “but putting together a team that thrives has been exciting.”

Suresh S. Ramalingam, MD, who succeeded Curran as executive director at Winship, says Curran’s impact on the field has been far-reaching, including optimizing treatment in patients with non–small cell lung cancer (NSCLC) and advocating for combined modality approaches as the longtime leader of NRG Oncology.

In the case of NSCLC, in 2011 Curran and colleagues waded into a debate about the optimal treatment for the relatively common but also heterogenous cancer type. At issue was whether sequential delivery of chemotherapy followed by thoracic radiotherapy was preferable versus concurrent delivery. In the phase 3 RTOG 9410 trial (NCT01134861) of more than 600 patients with NSCLC, Curran and colleagues showed that concurrent treatment significantly increased 5-year survival rates, leading to improvements in treatment for the roughly 50,000 Americans diagnosed with NSCLC each year.

In another widely cited phase 3 study, RTOG 9508 (NCT00002708), Curran showed that whole-brain radiotherapy combined with stereotactic boost treatment improved functional autonomy and survival in patients with single unresectable brain metastases. His work evaluating combined modalities has led to improved outcomes or modalities in several cancer types, including improved survival in anaplastic thyroid carcinoma.

Yet, even as his name appeared in major studies in big-name journals, Curran made time to extend his cooperative approach to patient care too.

“Despite his leadership roles that kept him busy, he was always available for his patients,” Ramalingam said. “He would always call me after seeing any mutual patient to update me on his recommendations. When things were not going well for a patient, he would always make the call to me to determine if anything else could be done to help that particular patient.”

Corn notes that Curran treated every patient the same—with the utmost dignity. When they worked together in Philadelphia, the hospital treated a sizable number of homeless people.

“There was just no way he would ever treat them differently than, say, a donor’s brother who came in,” Corn said.

Curran is a father of 2 daughters and 2 sons. His oldest daughter is a filmmaker, and his other daughter is finishing up graduate school in art history. His elder son is in college studying business, and his younger son is in high school. His wife of 15 years, Laura, is a computer software programmer. This past July 4, Curran became a grandfather for the first time.

Though Curran has had a career in the sciences, the arts have also played an important role in his life. Corn says that Curran has an obsessive love of jazz music. He remembered one time when Curran reported being tired from the night before. What kept him up so late? He had been at a jazz club.

Corn recalled Curran saying, “I just got this urge to hear some jazz.”

Like Curran’s love of running, his love of jazz started early.

“There was a jazz club called Sandy’s in my childhood neighborhood, which brought in the best jazz musicians from around Boston and beyond, and I hung out there whenever I could sneak in during high school and college,” he said.

In Philadelphia, he was friends with the owners of a bar that became the launchpad for 3-time Grammy winner Jill Scott. His favorite concert of all time was seeing Miles Davis play unannounced and unaccompanied at an outdoor waterfront concert in Philadelphia on Independence Day in 1984.

“Why do I love jazz? I never forget how that music makes me feel,” he said.

Curran is a voracious reader. He reads every short story in 

plus James Joyce’s and William Faulkner’s shorter works and as many contemporary short stories he can find.

“You have a tight narrative, you get to the point,” he said. “You have your crisis, your climax, your resolution, but you just have to do it with fewer words. So I think the words are more precious.”

One of the traits that has helped Curran succeed— whether in the clinic or on the track—has been his sense of discipline. He learned about discipline through one of his mentors, his childhood priest John D’Arcy.

“He was just a very disciplined man and a tremendous influence on me when I was very young,” Curran recalled.

D’Arcy, who later became the bishop of Fort Wayne-South Bend in Indiana, is known for sounding the alarm on sexual abuse of children in the Catholic Church, which resulted in the 2015 film, 

Curran says discipline often has a negative connotation, suggesting a lack of joy or pleasure. He does not see it that way.

“To me, discipline is a means to an end,” he said. “You’re not going to get satisfaction out of most things you do unless you apply some discipline to it, and that can be sports, hobbies, your work relationships, or anything.”

It was discipline that helped Curran become a lifelong runner and discipline that gave him the strength to grit his way through those tough early years as a teacher. Discipline fortified him during impossibly long days as a resident, and discipline helped etch his place at the top of his field.

In short, though he always had the potential to be an overachiever, his sense of discipline turned his potential into reality. His parents, however, would likely say that he simply met their high expectations for him. Like many working-class people, Curran’s parents, a machinist and a homemaker, harbored sky-high hopes for their high-achieving son, but they were “the extreme opposite of pushy parents,” he said.

Yet, when Curran called to say he had been accepted into medical school, his father responded in a way that still chokes Curran up.

“What I expected was some version of, ‘Congratulations,’ some polite version of ‘It’s about time,’ ” he said. “What he said instead was, ‘Medicine is very lucky to have you.’ ”

Walter J. Curran Jr, MD, always had the potential to be an overachiever, but his
sense of discipline turned that potential into reality.

Jared Kaltwasser

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