Carl H. June, MD, FAACR, Receives 2023 AACR Award for Lifetime Achievement in Cancer Research

Carl H. June, MD, FAACR, a Fellow of the AACR Academy and the Richard W. Vague Professor in Immunotherapy, director of the Center for Cellular Immunotherapies, and director of the Parker Institute for Cancer Immunotherapy in the Perelman School of Medicine at the University of Pennsylvania has been honored with the 2023 American Association for Cancer Research (AACR) Award for Lifetime Achievement in Cancer Research.

The award was established to honor an individual who has made significant fundamental contributions to cancer research, either through a single scientific discovery or a body of work. These contributions, whether in research, leadership, or mentorship, must have had a lasting impact on the cancer field and must have demonstrated a lifetime commitment to progress against cancer.

June will receive the award during the annual meeting of the AACR in Orlando, Florida, in April (14 – 19).

Groundbreaking work
A pioneer in the emerging field of immunotherapies, June is recognized for his groundbreaking work in developing the first gene-edited cell therapy for cancer and for demonstrating that adoptive T-cell therapy can induce remission and in some cases cure patients with advanced cancer.

Following his early report of synthetic T-cell activation nearly 30 years ago, June successfully developed a method of producing chimeric antigen receptor (CAR) T-cells to treat refractory and chronic lymphocytic leukemia. [1]

In essence, CARs, which consist of a T-cell activating domain (which typically includes the zeta chain of the CD3 complex) and extracellular immunoglobulin-derived heavy and light chains to direct specificity, are synthetic receptors that redirect the specificity, function, and metabolism of T-cells. [2] 

Patient specific
The technology, which involves the genetic reengineering of a patient’s own T-cells to combat their disease, is among the first gene transfer therapy techniques developed in the 1990s, to redirect the specificity of T cells with the use of T-cell receptors or CARs.

In simple terms, these CARs are uniquely engineered receptors that graft a defined specificity onto an immune effector cell, typically a T cell, and augment T-cell function. After infusion, these CAR T-cells engraft and undergo extensive proliferation in the patient where they will be able to kill many tumor cells.  In addition, these CAR T-cells may promote immune surveillance to prevent tumor recurrence through antigen release, by assisting tumor-infiltrating lymphocytes to attack tumors, or by their own persistence.

This technology has, since the early development of this approach, demonstrated sustained success in cancer patients and has shown tremendous promise for the treatment of hematologic malignancies. Today it has also received a breakthrough therapy designation for the treatment of pediatric acute lymphoblastic leukemia.[3][4]

Early beginning
June was the first to use leukapheresis and subsequent genetic reengineering of isolated T-cells to specifically recognize and kill antigens over-expressed in B cell malignancies such as the B cell antigen CD19 (cluster of differentiation 19). On account of their specificity for identifying and targeting CD19-expressing B cells for T-cell mediated cell death June named these modified T-cells CART-19 cells.

Response rates for patients receiving such CAR T-cell therapy have approached 90% for both adult and pediatric acute lymphoblastic leukemia and nearly 50% for chronic lymphocytic leukemia patients. Given the success of these preliminary results, additional ongoing studies have been devoted to utilizing CAR T-cell technology for the treatment of other hematologic malignancies including various forms of lymphoma and myeloma.

Precision Medicine
Immunotherapy has become a powerful clinical strategy for treating cancer and today there are now six U.S. Food and Drug Administration (FDA-) approved CAR T-cell therapies for multiple blood cancers, including, most recently, two approvals for multiple myeloma. Some of the earliest patients treated have experienced long-lasting remissions stretching past 10 years. This form of precision medicine represents the first therapy ever developed entirely in an academic setting to receive breakthrough therapy designation by the FDA. [5]

Ongoing research
Results in the clinic have helped define the major challenges that must be met to make engineered T-cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors.

The combination of genetic engineering and synthetic biology, the hallmarks of June’s work, offers a wide range of new possibilities to design and program T-cells and subsequent T-cell therapies with enhanced functions.

As part of the work, researchers are developing mechanisms designed to increasing the efficacy (prevention of antigen escape) and safety (reduction of on-target and off-tumor activity) of novel CAR therapies. This approach may include combinatorial targeting and Boolean logic–gated T-cells that only recognize either one of two different antigens or both antigens only. [6]

Amon these new strategies researchers are also engineering T-cells that can be used as a launching pad to reach the tumor microenvironment. These new approaches may include expressing costimulatory ligands on the surface of CAR T cells [7] or secreting cytokines (such as Il-12) or other molecules. [8] [9]

For example, in preclinical studies researchers have demonstrated that treatment with CD19-specific, chimeric antigen receptor (CAR)-modified T-cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease.

The safe use of T-cell therapies may be further increased with the use of so-called controllable suicide switches such as inducible caspase 9 and truncated epidermal growth factor receptor (EGFRt) [10].

Beyond cancer
June’s seminal contributions have not only led to the establishment of CAR T-cell therapy for blood cancers; applications in chronic infections and autoimmune diseases are now being investigated.

Together with his research team at Penn Medicine’s Abramson Cancer Center June continue to report on numerous aspects of fundamental CAR T-cell biology, while remaining at the forefront of developing the next generation of CAR T-cell therapies.  His ongoing research continues to be centered on further understanding lymphocyte activation mechanisms and T cell signaling in an effort to design novel immunotherapy-based treatments for viral infections as well as cancer.

In addition to his reachers, June is currently a senior editor for Cancer Immunology Research and an editorial board member for Blood Cancer Discovery, and was previously an associate editor for Cancer Research (2007-2009).

Trailblazer
“June is a trailblazer in the field of cancer immunotherapy whose scientific expertise and vision for the field have been crucial to pivotal scientific discoveries that have improved and saved many lives from cancer,” said Margaret Foti, Ph.D., MD (hc), chief executive officer of the AACR.

“His work has transformed the treatment of hematologic malignancies and holds great promise for many other types of cancer. We are grateful for Dr. June’s numerous scientific contributions and are thrilled to recognize him with this prestigious award,” Foti concluded.

Other awards
June has received many awards throughout his illustrious career, including the 2015 AACR-Cancer Research Institute (CRI) Lloyd J. Old Award in Cancer Immunology, the Keio Medical Science Prize (2022), the American Society of Clinical Oncology David A. Karnofsky Memorial Award and Lecture (2017), the Novartis Prize in Immunology (2016), the Award for Distinguished Research in Biomedical Sciences from the Association of American Medical Colleges (2015), the E. Donnall Thomas Prize from the American Society for Blood and Marrow Transplantation (2015), the Paul Ehrlich and Ludwig Darmstaedter Prize from the Paul Ehrlich Foundation (2015), the Hamdan Award for Medical Research Excellence (2014), the Association for the Advancement of Blood & Biotherapies Karl Landsteiner Memorial Award (2014), the Philadelphia Award (2013), the Cancer Research Institute William B. Coley Award for Distinguished Research in Basic and Tumor Immunology (2012), the Alliance for Cancer Gene Therapy Joan Miller and Linda Bernstein Gene Therapy Ovarian Cancer Award (2008), the Bristol-Myers Squibb Freedom to Discover Award (2005-2009), the Federal Laboratory Consortium Award for Excellence in Technology Transfer (2005), the Keio Medical Science Prize (2022) and the Leukemia and Lymphoma Society of America Lifetime Achievement Award (2002).

June is an elected fellow of the American Academy of Arts and Sciences (2014) and an elected member of the National Academy of Medicine (2012) and the National Academy of Science (2020).

June received his undergraduate degree in biology at the United States Naval Academy and his medical degree from Baylor College of Medicine. He completed a research fellowship at the World Health Organization Immunology Research and Training Center in Geneva, Switzerland, and a fellowship in oncology at the University of Washington and Fred Hutchinson Cancer Center in Seattle.

Reference
[1] June CH, Sadelain M. Chimeric Antigen Receptor Therapy. N Engl J Med. 2018 Jul 5;379(1):64-73. doi: 10.1056/NEJMra1706169. PMID: 29972754; PMCID: PMC7433347.
[2] Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, Nagase F, Kurosawa Y. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun. 1987 Dec 31;149(3):960-8. doi: 10.1016/0006-291x(87)90502-x. PMID: 3122749.
[3] Sadelain M, Rivière I, Riddell S. Therapeutic T cell engineering. Nature. 2017 May 24;545(7655):423-431. doi: 10.1038/nature22395. PMID: 28541315; PMCID: PMC5632949.
[4x] Sadelain M, Brentjens R, Rivière I. The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol. 2009 Apr;21(2):215-23. doi: 10.1016/j.coi.2009.02.009. Epub 2009 Mar 25. PMID: 19327974; PMCID: PMC5548385.
[5] Riley RS, June CH, Langer R, Mitchell MJ. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov. 2019 Mar;18(3):175-196. doi: 10.1038/s41573-018-0006-z. PMID: 30622344; PMCID: PMC6410566.
[6] Lim WA, June CH. The Principles of Engineering Immune Cells to Treat Cancer. Cell. 2017 Feb 9;168(4):724-740. doi: 10.1016/j.cell.2017.01.016. PMID: 28187291; PMCID: PMC5553442.
[7] Zhao Z, Condomines M, van der Stegen SJC, Perna F, Kloss CC, Gunset G, Plotkin J, Sadelain M. Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell. 2015 Oct 12;28(4):415-428. doi: 10.1016/j.ccell.2015.09.004. PMID: 26461090; PMCID: PMC5003056.
[8] Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF, Sadelain M, Brentjens RJ. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood. 2012 May 3;119(18):4133-41. doi: 10.1182/blood-2011-12-400044. Epub 2012 Feb 21. PMID: 22354001; PMCID: PMC3359735.
[9] Hu B, Ren J, Luo Y, Keith B, Young RM, Scholler J, Zhao Y, June CH. Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18. Cell Rep. 2017 Sep 26;20(13):3025-3033. doi: 10.1016/j.celrep.2017.09.002. PMID: 28954221; PMCID: PMC6002762.
[10] Paszkiewicz PJ, Fräßle SP, Srivastava S, Sommermeyer D, Hudecek M, Drexler I, Sadelain M, Liu L, Jensen MC, Riddell SR, Busch DH. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest. 2016 Nov 1;126(11):4262-4272. doi: 10.1172/JCI84813. Epub 2016 Oct 17. PMID: 27760047; PMCID: PMC5096899.

Featured Image: Cancer Immunotherapy. Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Nanomedicine researchers are creating personalized cancer vaccines by loading neoantigens identified from the patient’s tumor into nanoparticles. When presented with immune stimulants, this activates the patient’s own immune system, leading to expansion of tumor-specific cytotoxic T cells. Photo courtesy: © 2016 – 2023 National Cancer Institute on Unsplash. Used with permission

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