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Chimeric Antigen Receptor T-Cell Therapy
The beginnings of “Immunotherapy” can arguably be traced back to the ancient Egyptians. They, like James Paget, Wilhelm Busch, and Friedrich Fehleisen in the mid-1800s, observed that some cancer patients experienced tumor regression after suffering from infections. By the late 1800s, the “Father of Immunotherapy” William Coley had started administering injections composed of dead Streptococcus pyogenes and Serratia marcescens as a crude form of immunotherapy. His work was carried forward by his daughter, Helen Coley Nauts, and eventually, Lloyd Old. Old worked on the antitumor effects of the Bacillus Calmette-Guérin vaccine and earned the title “Father of Modern Cancer Immunology.” Today, the domain of immunotherapy has delivered several new armaments in the war against cancer. These include targeted therapies using monoclonal antibodies, cytokine therapy (interferon-α [IFN-α] and interleukin-2 [IL-2]), immune checkpoint inhibitors (anti-CTLA-4, anti-PD1, and anti-PD-L1), oncolytic viruses (T-Vec/talimogene laherparepvec), cancer vaccines, immune costimulatory molecules, and adoptive cell therapy (ACT). Founded at the cross-roads of genetic engineering and molecular biology, ACT can be of various types: tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor (TCR)-engineered T-cell therapy, natural killer cell therapy, or chimeric antigen receptor (CAR) T-cell therapy. Among these, CAR T-cells have received the most attention and shown the most promise.
In TIL therapy, TILs are extracted from a patient’s tumor biopsy specimen and then cocultured with autologous dendritic cells exposed to neoantigens present in the patient’s tumor. TILs recognizing the patient-specific neoantigens are then selected, expanded in vitro using IL-2, and then infused back into the patient. TIL therapy has shown some promise in melanomas, colorectal cancer, and breast cancer. TCR T-cell therapy is less invasive than TIL therapy as the required lymphocytes are sourced from the patient’s peripheral blood and are more proliferative than TILs. After extraction, purification, and activation, the T-cells are genetically modified by retroviral/lentiviral transduction or nonviral methods (such as electroporation or transposon delivery systems) to express cell-surface receptors targeting specific antigens. These are still natural receptors and can detect antigens from anywhere in the cell, as long as they are presented to them by the major histocompatibility complex (MHC) molecules. Trials have shown some benefit in sarcomas and melanomas. However, they can only target peptide antigens and, to be effective, require adequate MHC expression by the patient’s tumor cells. TCRs may also cross-react with endogenous antigens and, hence, carry a risk of induced severe autoimmunity. The more advanced CAR T-cells have the advantage that they are not MHC restricted and can recognize both protein and nonprotein antigens independently of the MHC, without antigen processing/presentation by the target cells. Thus, they can be engineered against a wider array of targets. The “chimeric” in CARs refers to the fact that these combine both antigen-binding and T-cell activation functions into a single synthetic receptor. The antigen binding in CAR T-cells is achieved through the use of specific recombinant antibodies in the extracellular domain, earning them the nickname “T-bodies.” Just like TILs, TCR and CAR T-cells are also clonally expanded in vitro and, then, after subjecting the patient to a lymphodepleting chemotherapy, infused back into the patient, often with in vivo IL-2 support. The steps involved in CAR T-cell therapy are shown in [Fig. 1].
“Immunotherapy” was the ASCO “Advance of the Year” in 2016 and 2017, and in 2018, the honor went to CAR T-cell research. Yet, the work had started much earlier, with Zelig Eshhar proposing the concept in the early 1980s and, subsequently, engineering the first CAR T-cell. First-generation CAR T-cells coupled an extracellular single-chain variable fragment (scFv) with an intracellular CD3-ξ, (zeta) signaling domain. A scFv should not be thought of as an antibody fragment; it is a fusion protein made by joining variable regions of light (VL) and heavy (VH) immunoglobulin chains with a peptide linker. Michel Sadelain was the first to conduct clinical trials in this area and used second-generation CAR T-cells with additional co-signaling molecules such as 4–1BB or CD28. He called these cells “living drugs,” capable of greater in vivo clonal expansion and longer persistence in circulation. In 2017, two CAR T-cell therapies received the Food and Drug Administration (FDA) approval—tisagenlecleucel and axicabtagene ciloleucel, both of which target CD19 ([Table 1]). The evolution of CAR T-cell therapy is depicted in [Fig. 2].
28 May 2021 (online)
© 2021. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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