Emily Ensley

Background: Solid tumors are abnormal masses that do not contain fluid.¹ Three major categories of solid tumors include melanoma, carcinoma, and sarcoma, and prognosis depends primarily on the tumor type, its location, and timing of diagnosis. Many solid tumors are resistant to current therapeutic options.^2-6 Cancer immunotherapies such as adoptive T cell therapy are a promising personalized treatment option for many solid tumors. However, challenges with identifying suitable tumor specific antigens, avoiding off target therapeutic effects and overcoming an immunosuppressive tumor microenvironment still desperately need to be addressed.⁶

Objective: In this narrative review, we explored different methods for enhancing CAR-T cell therapies to treat solid tumors.

Search methods: An online search in the PubMed database was conducted from 2018 to 2023 using phrases: “Adoptive T cell therapy”, “TCR-T cell therapy”, “solid tumors”, “MAGE therapy”, and “Ny-ESO therapy”.

Results: To assess the binding mechanism of extended peptides on HLA-Class I molecules, researchers isolated and expanded NY-ESO-_160–72-HLA-B*07:02 reactive CD8+T cells from PBMCs of patients with metastatic melanoma vaccinated with NY-ESO-1. They found that docking mechanisms of clinically significant extended peptide epitopes vary between distinct T cell populations.⁹ In another study, researchers used RNAi to silence endogenous TCRs and introduced a codon optimized MAGE-A4 specific TCR to create a TCR-T cell therapy specific for MAGE-A4+ tumors.¹⁰ Another group of researchers sought to generate a single variable domain TCR using only the variable β domain that can be used to generate mono or bispecific CAR and TCR constructs to be used in adoptive T cell therapy.¹¹ A separate study developed a MAGE-A4 specific TCR vector that can function on both CD4+ and CD8+ T cell subsets allowing for enhanced tumor killing, T cell proliferation, and widening the immune response through activation of antigen presenting cells.¹² Lastly, a clinical trial was conducted to assess the safety and efficacy Afami-cel, an HLA antigen restricted T cell therapy targeting MAGE-4, in patients suffering from relapsed/refractory melanoma, head and neck cancer or ovarian cancer.¹³

Conclusion: Multiple engineering strategies are currently being studied to enhance adoptive T cell therapy for treating solid tumors. In this literature search, we found that understanding the TCR binding mechanisms to peptide:MHC complexes, silencing endogenous TCRs in engineered TCR-T cell therapies, using single variable domains to enhance CAR and TCR  vector design, and generating coreceptor independent TCR vectors are all promising strategies for enhancing solid tumor elimination by adoptive T cell therapies. We also assessed a pilot clinical trial that Afami-cell, a MAGE-A4 specific TCR T cell therapy, is a promising treatment for MAGE-A4+ tumors that have clinically unmet needs, such as metastatic synovial sarcoma. Overall, further research into these strategies will open the door for more therapeutic options for solid tumors with clinically unmet needs.^9-13

Works Cited.

1. NCI Dictionary of Cancer Terms. National Cancer Institute. Published February 2, 2011. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/solid-tumor
2. Gazendam AM, Popovic S, Munir S, Parasu N, Wilson D, Ghert M. Synovial Sarcoma: A Clinical Review. Current Oncology. 2021;28(3):1909-1920. doi:https://doi.org/10.3390/curroncol28030177
3. Davis LE, Shalin SC, Tackett AJ. Current state of melanoma diagnosis and treatment. Cancer Biology & Therapy. 2019;20(11):1366-1379. doi:https://doi.org/10.1080/15384047.2019.1640032
4. Kittler H. Evolution of the Clinical, Dermoscopic and Pathologic Diagnosis of Melanoma. Dermatology Practical & Conceptual. 2021;11(Suppl 1):e2021163S. doi:https://doi.org/10.5826/dpc.11S1a163S
5. Raimondi S, Suppa M, Gandini S. Melanoma Epidemiology and Sun Exposure. Acta Dermato Venereologica. 2020;100(11):adv00136. doi:https://doi.org/10.2340/00015555-3491
6. Greenbaum U, Dumbrava EI, Biter AB, Haymaker CL, Hong DS. Engineered T-cell Receptor T Cells for Cancer Immunotherapy. Cancer Immunology Research. 2021;9(11):1252-1261. doi:https://doi.org/10.1158/2326-6066.cir-21-0269
7. Schooten E, Di Maggio A, van Bergen en Henegouwen PMP, Kijanka MM. MAGE-A antigens as targets for cancer immunotherapy. Cancer Treatment Reviews. 2018;67:54-62. doi:https://doi.org/10.1016/j.ctrv.2018.04.009
8. Chan KF, Gully BS, Gras S, et al. Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide. Nature Communications. 2018;9(1). doi:https://doi.org/10.1038/s41467-018-03321-w

9. Chan KF, Gully BS, Gras S, et al. Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide. Nature Communications. 2018;9(1). doi:https://doi.org/10.1038/s41467-018-03321-w
10. Sun Q, Zhang X, Wang L, et al. T-cell receptor gene therapy targeting melanoma-associated antigen-A4 by silencing of endogenous TCR inhibits tumor growth in mice and human. Cell Death & Disease. 2019;10(7). doi:https://doi.org/10.1038/s41419-019-1717-8
11. Oh J, Warshaviak DT, Mkrtichyan M, et al. Single variable domains from the T cell receptor β chain function as mono- and bifunctional CARs and TCRs. Scientific Reports. 2019;9(1):17291. doi:https://doi.org/10.1038/s41598-019-53756-4
12. Davari K, Holland T, Prassmayer L, et al. Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy. Journal for ImmunoTherapy of Cancer. 2021;9(3):e002035. doi:https://doi.org/10.1136/jitc-2020-002035
13. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nature Medicine. 2023;29(1):104-114. doi:https://doi.org/10.1038/s41591-022-02128-z