Jeffrey S Weber’s passing on 18 August 2024 brought forth a wave of emotions and fond memories for a colleague considered to be one of the major forces in the advancement of tumor immunology and immunotherapy. Known for his keen wit, sharp insights and gracious personality, Jeff pioneered novel science, led practice-changing clinical trials and mentored the next generation of investigators. His leadership shepherded the field of immuno-oncology into the prominence it now holds. His contributions to the development of immune-checkpoint blockade (ICB), adoptive cell transfer and neoantigen targeting, among others, have and will continue to inform the expansion of these approaches into multiple types of cancer.

Jeff was born in Brooklyn, New York, in 1952 and New York City never left him. Jeff attended Columbia University graduating with a BA in Biology and went on to obtain his MD from the New York University Medical Scientist Training Program. He completed his PhD at Rockefeller University in the laboratory of James E Darnell, Jr, where his thesis work on RNA biology of adenoviral infection was published in Cell. Jeff then pursued an internship and residency in medicine at the University of California (UC), San Diego. During his time there, he met Linda Olsen and married soon after.

He then moved to the National Cancer Institute (NCI). After spending a year in the Medicine Branch, Jeff moved to the Surgery Branch where he had increasing roles of responsibility and success. During this time, Jeff was mentored by some of the pre-eminent leaders of the field, perhaps most notably Steven Rosenberg. At the NCI, Jeff published broadly from investigations surrounding the preclinical impact of cytokine therapy in murine models and the role of major histocompatibility complex molecules in response, to clinical reports of trials involving cytokines such as interleukin (IL)-2 to IL-6, IL-15 and granulocyte-macrophage colony-stimulating factor as well as adoptively transferred tumor-infiltrating lymphocytes (TILs) and various cancer vaccines. For over 3 years, he shared a two-person, 6-foot biosafety cabinet with Bernie Fox. During this time, Jeff often lectured his laboratory partner about the shortcomings of American cars, human nature, not wearing bowties and jokingly acted as if he were hearing his confessions. Though Jeff never quite figured out the proper place to store the serological pipettes, a valued friendship developed that only grew stronger over the past four decades.

…even at that relatively early time in his career, Jeff was one of those rare individuals who combined deep insight into clinical problems with an extraordinary talent for pursuing basic laboratory research in cancer immunology. His contributions played an important role in the development of modern immunotherapy. – Steven Rosenberg, MD, PhD, Chief of the Surgery Branch, NCI

Following his time as a Senior Investigator in Tumor Immunology at NCI, Jeff moved back to California initially at UC Irvine before an extended tenure at the University of Southern California (USC). At USC, Jeff established the National Institutes of Health (NIH) funded Specialized Programs of Research Excellence (SPORE) infrastructure to study cancer immunology and melanoma, building the multidisciplinary teams that are a hallmark of his legacy. He continued to drive the field of peptide vaccination for cancer, particularly surrounding cancer testis antigens and the integration of novel adjuvants including but not limited to IL-12, gaining international recognition for his work with high-dose cytokine-based therapies and investigating combinations with chemotherapy. Jeff was one of the first to investigate the clinical consequences of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade, alone and with vaccination, and published some of the first reports surrounding the autoimmune-like consequences that we all now recognize as immune-related adverse events (irAEs). He was, and remained, perhaps the pre-eminent expert in describing and proposing management guidelines for irAEs in the clinic.

After an extended period of tremendous success at USC, Jeff was recruited to the Moffitt Cancer Center. There, in conjunction with Vernon Sondak and Jim Mulé, he developed and expanded SPORE and other team-based research through several iterations of local efforts in adoptive cell therapy. Jeff became one of the leading investigators to advance the therapeutic potential of anti-CTLA-4 antibody with ipilimumab through phase II and III clinical trials. He was a leading investigator for all the trials investigating anti-PD-1 antibodies in melanoma and was a major force behind initial investigations of adjuvant systemic management with ICB. He led the seminal study Checkmate-238, demonstrating the role for nivolumab in stage III melanoma. During this period, Jeff also was a leader in the development of BRAF-targeted agents in melanoma as the senior investigator in the phase III trial of dabrafenib plus trametinib. Jeff was also instrumental in the eventual development of TIL as a therapeutic modality in melanoma.

In 2015, Jeff joined the NYU Grossman School of Medicine as Deputy Director of the Laura and Isaac Perlmutter Cancer Center (PCC) and Director of its Experimental Therapeutics programme. In 2018, Jeff helped PCC secure NCI comprehensive status and, in 2019, a melanoma SPORE. Jeff continued to lead the field of novel immune oncology approaches, particularly surrounding neoantigen vaccine development in melanoma. He designed and led the phase II trial of pembrolizumab, with or without the individualised neoantigen therapy mRNA-4157/V940, with broad relevance as a novel therapeutic paradigm across cancer.

Convincing Jeff to move to NYU was the best decision I have ever made in my career, if not my life! Jeff pushed us to the next level. He remarkably improved our game. His positive impact on all of us personally and professionally is immeasurable. Facing the unimaginable at the end, Jeff did what he enjoyed the most, work. He worked hard—to the last day—to make sure there will be continuity of the progress made in the field – Iman Osman, MD, Director, Interdisciplinary Melanoma Program, NYU Langone Health

The span and breadth of Jeff’s career were expansive and highly impactful. Throughout his various stops in his academic journey, Jeff constantly maintained excellence in his and his team’s research, maintaining continuous NIH funding his entire career. He was one of the few investigators whose own work would directly be accessed by industry and advanced into registrational intent trials and eventually Food and Drug Administration-approved treatment indications. It is notable that his investigator-initiated, randomised clinical trial of adding anti-IL-6 antibody to ICB is poised to establish a new framework for toxicity consideration and management in patients getting combination checkpoint approaches. As the world’s expert in immune-related toxicity, Jeff was also an essential resource in the initial response to the COVID-19 pandemic, collaborating with Paolo Ascierto to rapidly stand-up protocols in Italy to study the role of anti-IL-6 agents and to distribute the most up to date information available on patient management strategies across the world via the Society for Immunotherapy of Cancer (SITC).

Jeff had great achievements and received recognition as well as numerous awards during his career. Jeff was considered one of the most reliable and constructive Editorial Board members and manuscript reviewers in the field. This included at the Journal for ImmunoTherapy of Cancer (JITC) where, in 2023, he was recognized with the Pedro J Romero Service to JITC Award for outstanding contributions to the journal. In addition, we would call attention to his induction as a Fellow of the Academy of Immuno-Oncology (FAIO) by SITC. Jeff was deeply moved by this honor. In his acceptance speech, he made two particularly salient points. The first centered on the price to be paid for excellence, recounting the sacrifices his wife and children made as he was pursuing his career. His second point was that everyone needs a rabbi in life. He meant this not in the religious sense, but rather that everyone needs a mentor. He recounted his good fortune in having wonderful mentors throughout his career and stressed that, as we gain the life and career knowledge that comes with experience, we must take on the job of mentoring. We would highly recommend taking a moment to review his induction speech on the SITC’s FAIO website where Jeff made these points.

Beyond patient advocacy, leadership and achievement, Jeff’s career was punctuated by mentorship. His legacy is as one of the best team builders and mentors in our field. At every stop, Jeff fostered and enhanced the careers of several now high-profile investigators including Omid Hamid, Geoffrey Gibney and Janice Mehnert. Among the many mentees in his laboratory, Jeff supported the growth of Amod Sarnaik, who has gone on to spearhead the development of lifileucel as the first approved adoptively transferred cell product for solid tumors. Jeff was lauded as an educator for physicians, nurses and all students.

A great friend, amazing mentor, brother, leader. He was always leading by example. Always communicating in the future tense. Precise to a point, expert. Dry wit. Tactical. As his apprentice, he insisted on 6 AM education on immunology, trials, life. I am so grateful for his guidance, mentorship, friendship. It was irreplaceable. – Omid Hamid, MD, Director of the Melanoma Center and Phase I Immuno-Oncology Program, The Angeles Clinic and Research Institute

Above all, Jeff Weber was a family man who was aware of the support and sacrifices made to ensure his success. He leaves behind Linda, his wife of 41 years, as well as daughters Katie and Hannah. Many of us cherish the place that Jeff held in our lives on a personal level. We will remember him for his encyclopedic knowledge of the newest restaurants across the New York boroughs, his love of history, particularly the details of World War II, and the many personal conversations we each had with him. Jeff was a world citizen who easily established global friendships. He taught by example to appreciate everything that a comprehensive and amazingly well-lived life could offer. Forever a kind person, witty and humorous but also direct with high expectations of those on whom he had placed them. To have received such expectations was an honor to many of us and only made us better as we strived to achieve the success he was guiding us toward.

Today, we struggle to find a resolution to the void in our lives that Jeff leaves behind. Jeff truly showed us what a roadmap for a successful life and career looks like. In the mode of the venerable World War II generals that he revered, he worked diligently throughout his final days to arrange a future for his patients’ and our fields’ success. We have been given our marching orders and begin this future knowing that it will, although without the wit and elegance of Jeffrey S Weber, live on through his colleagues and mentees.

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