Abstract
Immune checkpoint inhibitors have redefined the treatment of cancer, but their efficacy depends critically on the presence of sufficient tumor-specific lymphocytes, and cellular immunotherapies develop rapidly to fill this gap. The paucity of suitable extracellular and tumor-associated antigens in solid cancers necessitates the use of neoantigen-directed T-cell-receptor (TCR)-engineered cells, while prevention of tumor evasion requires combined targeting of multiple neoepitopes. These can be currently identified within 2 weeks by combining cutting-edge next-generation sequencing with bioinformatic pipelines and used to select tumor-reactive TCRs in a high-throughput manner for expeditious scalable non-viral gene editing of autologous or allogeneic lymphocytes. “Young” cells with a naive, memory stem or central memory phenotype can be additionally armored with “next-generation” features against exhaustion and the immunosuppressive tumor microenvironment, where they wander after reinfusion to attack heavily pretreated and hitherto hopeless neoplasms. Facilitated by major technological breakthroughs in critical manufacturing steps, based on a solid preclinical rationale, and backed by rapidly accumulating evidence, TCR therapies break one bottleneck after the other and hold the promise to become the next immuno-oncological revolution.
Highlights
The advent of immunotherapy was a crucial advance for medical oncology: for the first time ever, five-year survival became feasible for patients with highly lethal solid tumors, such as advanced melanoma and non-small-cell lung carcinoma (NSCLC) [1,2,3,4]
The first source of tumor-specific T cells have been the patient’s own tumor-infiltrating lymphocytes (TIL), which can be isolated from tumor tissue, expanded using cytokines together
Immunization of transgenic humanized mice with human tumor-associated antigens (TAA) to circumvent self-tolerance, amino acid substitutions, T-cell display systems and other methods are available to engineer higher-affinity TCRs [33,34,35,36,37], and pose a significant safety risk, as illustrated by a clinical trial of a high-avidity TCR against the carcinoembryonic antigen (CEA): three patients nearly died of severe inflammatory colitis, because the transduced T cells attacked normal colonic epithelial cells, which express CEA, albeit at lower levels [38]
Summary
The advent of immunotherapy was a crucial advance for medical oncology: for the first time ever, five-year survival became feasible for patients with highly lethal solid tumors, such as advanced melanoma and non-small-cell lung carcinoma (NSCLC) [1,2,3,4]. Immunization of transgenic humanized mice with human TAA to circumvent self-tolerance, amino acid substitutions, T-cell display systems and other methods are available to engineer higher-affinity TCRs [33,34,35,36,37], and pose a significant safety risk, as illustrated by a clinical trial of a high-avidity TCR against the carcinoembryonic antigen (CEA): three patients nearly died of severe inflammatory colitis, because the transduced T cells attacked normal colonic epithelial cells, which express CEA, albeit at lower levels [38]. The essential tumorigenic role of many neoantigens (especially public ones, such as those generated by activating oncogene mutations) compared to TAA, that hinders antigen-loss as an evasion mechanism [21], the higher affinity of TCR directed against tumor-specific antigens (TSA) compared to TAA/CTA, and the better tumor penetration of TCR-T compared to CAR-T cells, are additional features of key importance for the treatment of solid tumors, but there are some critical bottlenecks to overcome first
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