Authored by: George M. Pikler, M.D., Ph.D., FACP
The aim of this overview is to introduce a paradigm-shifting cell immunotherapy modality in oncology, the chimeric antigen receptor T cell (CAR-T) therapy whose principle is to genetically engineer patient- or donor-derived T cellsin order to re-direct their immune response machinery to recognize and kill tumor cells expressing a specific target antigen. It has revolutionized the therapeutic landscape in the treatment of several hematologic malignancies. Since 2017, the Food and Drug Administration (FDA) has approved six CD19-targeted CAR-T cell therapies for the treatment of lymphomas, some forms of leukemia, and most recently for multiple myeloma with a BCMA-targeted antigen. All of these approved CAR-T cell therapies rely on a disarmed virus to deliver the genetic material into T cells to produce the CAR.
As depicted in Image 1, patient’s blood is drawn and its T cells, a type of white blood cell and components of our immune system, are harvested by pheresis and isolated. Then, the gene for a special receptor called a chimeric antigen receptor (CAR) is inserted into the T cells in the laboratory. Each CAR [Image 2] bridges the T cell membrane and has a modular design consisting of the antigen-binding domain, an external component that binds to the antigens that are overexpressed on the surface of cancer cells, a hinge and transmembrane domain, and an intracellular domain that transmits signals into the cell after the receptors interact with the antigens. This recognition activates anti-cancer immune pathways. The CAR T cells are then
expanded into the millions in the laboratory and infused back into the patient for treatment. The CAR T cells, if everything goes as expected, will continue to multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.
The application of CAR-T cell therapy for the treatment of solid tumors has been met with several challenges and limitations which several research institutions with expertise in the use of CAR T- cell therapy are actively researching ways to overcome.
One of the main limitations is that most of the proteins present in solid tumors that could be used as targets are also found at low levels on normal cells, making it difficult to specifically direct the CAR T cells against tumor cells and spare healthy ones. According to Crystal Mackall, M.D., director of the Parker Institute for Cancer Immunotherapy at Stanford University, perhaps the biggest barrier is “an age-old problem: tumor heterogeneity.” “In other words, solid tumors of the same cancer type can be molecularly quite different from patient to patient, and even within a particular patient.”
Other challenges include life-threatening toxicities (including neurological toxicity, cytokine release syndrome (CRS), tumor lysis syndrome and anaphylaxis), antigen escape, the poor in vivo expansion and persistence of adoptively transferred T cells, which necessitates lymphodepleting conditioning chemotherapy—a toxic regimen that limits patient eligibility. Scientists from the UCLA in collaboration with those from the University of Stanford and the University of Pennsylvania recently published a study showing that a synthetic IL-9 receptor allows CAR T cells to fight against cancer cells without the need for chemotherapy or radiation.1
In addition, the hostile tumor microenvironment (TME) of solid tumors can prevent the infused CAR T cells from reaching tumor cells. Other components of the microenvironment, such as immune-suppressing molecules produced by tumor cells or other immune cells, can cause CAR T cells to malfunction.
1 Kalbasi, A., Siurala, M., Su, L.L. et al. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature 607, 360–365 (2022).
Finally, the development and implementation of CAR-T cell therapy requires a complex workforce and currently its high cost is a barrier in itself for many patients.
A growing number of CAR-T cell therapies are being developed and tested in clinical studies (glioblastoma multiforme, 2 pancreatic cancer, 3_4 colorectal cancer 5) Part of this expansion is a product of researchers having identified additional antigens on tumor cells that might be good targets for CAR T cells.
Recently, another approach has been proposed: integrating CAR T cells with different types of immunotherapies to enhance its effectiveness. For example, CARs may be combined with certain checkpoint inhibitors, which limit tumor defense mechanisms against T cells.
It is expected that future CAR-T cell therapy regimens will target several diverse molecules for a particular type of tumor, such that CAR T cells can efficiently recognize cancerous cells even if these undergo mutations in their target molecules.
2 Soler, D.C., Kerstetter-Fogle, A., McCormick, T.S. et al. Using chimeric antigen receptor T-cell therapy to fight glioblastoma multiforme: past, present, and future developments. J Neurooncol 156, 81–96 (2022)
3 Leidner, Rom, et al. Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. N Engl J Med 2022; 386:2012-2019
4 Maryam Sahlolbei, Mohsen Dehghani, et al. (2020) Evaluation of targetable biomarkers for chimeric antigen receptor T-cell (CAR-T) in the treatment of pancreatic cancer: a systematic review and meta-analysis of preclinical studies. International Reviews of Immunology, 39:5, 223-232.
5 Prenen H, Dekervel J, et al. Updated data from alloSHRINK phase I first-in-human study evaluating CYAD-101, an innovative non-gene edited allogeneic CAR-T in mCRC. Journal of Clinical Oncology. 2021;39 (3_suppl):74-.
George M.Pikler, M.D., Ph.D., FACP
Lead Oncology Advocate N1X10
Dr. Pikler graduated summa cum laude from the Central University of Ecuador School of Medicine in 1968. His postdoctoral training included an internship in internal medicine at Greater Baltimore Medical Center in Baltimore, MD, a residency in internal medicine and a doctoral degree in molecular medicine at the Mayo Clinic in Rochester, MN. The American Cancer Society awarded him a fellowship in medical oncology and hematology at M.D. Anderson & Tumor Institute in Houston, TX.
With training certifications in internal medicine and oncology, Dr. Pikler and his family moved to Tulsa, OK where he established and was the President of Cancer Specialists, Inc, a boutique oncology-hematology clinical research private practice. In addition, he was the chief of the oncology at Hillcrest Medical Center, a teaching hospital for 20 years and associate professor of medicine, oncology-hematology at the University of Oklahoma, Tulsa Medical College. He was one of the founders of the Southern Association of Oncology Practices and subsequently the National Medical Director for the International Oncology Network, AmerisourceBergen’s Oncology Division.