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Adaeze Ekwe, PhD
Junior Associate Editor
ISCT ESP Leadership Development Program

Cellular therapies have significantly evolved since inception as one of the most innovative and transformative approaches to treat diseases, offering new hope for patients with conditions previously deemed untreatable. The journey from early development to current advancements has resulted in significant breakthroughs with 85 approved genetically and non-genetically modified cell therapies to date for several indications ranging from hematological malignancies, corneal dystrophy to autoimmune disorders, and several other clinical trials underway [1].

However, the application of these therapies to treat solid cancers has proved more challenging thus far. The most notable of these therapies are the T-lymphocyte group encompassing chimeric antigen receptor (CAR) T cell therapies with ten therapies approved for various hematological cancers in multiple regulatory jurisdictions including the United States, Europe, Australia, Japan and China [1]. Despite the remarkable clinical success in blood cancers, these therapies have shown poor outcomes in solid cancers. Recent developments suggest that another group of T cell therapies have overcome some of the hurdles posed by solid tumors with the recent approval of AMTAGVI and TECELRA for advanced melanoma and sarcoma respectively by the United State Food and Drug Administration (FDA).

AMTAGVI (lifileucel) is a one-time tumor-infiltrating lymphocyte (TIL) therapy for patients with previously treated melanoma that has spread or cannot be removed by surgery. It is the first adoptive cellular therapy to be approved for a solid tumor following an open-label phase 2 trial in advanced melanoma patients with disease progression following checkpoint inhibitor therapy. The approval was based on lifileucel’s ability to provide 31.5% overall response rate in 73 patients, with complete response in 4.1% of patients, and responses lasting at least 12 months in 43.5% of responders [2, 3]. Continuous approval is contingent on the results of a confirmatory phase 3 trial which is currently underway.

TIL therapies are several decades in the making with and involve isolating immune cells from a patient’s tumor, expanding them in the laboratory and reinfusing them [4, 5]. TILs exploit the intrinsic ability of the immune cells present within the tumor to specifically recognize multiple tumor antigens and kill the cancer cells. Prior to infusion, patients undergo lymphodepletion to kill existing T cells; the expanded cells are subsequently co-infused with high-dose interleukin-2 (IL-2). As such, common adverse effects associated with TIL therapy include risk of lymphodepletion-related and IL-2 toxicities [6]. In addition, as cells are sourced from tumor tissues, patients with unresectable tumor tissues cannot benefit from this therapy. Several ongoing clinical trials are exploring the broader application of TIL therapies in other solid tumors such as non-small cell lung cancer (NCT04614103, NCT04032847) and carcinomas (NCT03083873, NCT06237881, NCT03108495), as well as combination TIL therapies with immune checkpoint inhibitors (NCT03645928).

TECELRA (afamitresgene autoleucel or afami-cel) is a gene-modified autologous T cell therapy expressing novel T cell receptor (TCR) that recognizes the MAGE-A4 antigen and the first TCR-engineered therapy for solid cancer. It was approved for the treatment of unresectable or metastatic synovial sarcoma in adult patients “who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, 6 or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen”. The overall response rate in 44 patients who participated in the SPEARHEAD-1 open-label phase 2 trial who received afami-cel was 43.2% with complete response in two patients (4.5%). In 39% of patients who responded, the duration of response was greater than 12 months [7, 8]. Clinical studies using TCR-engineered T cells alone or in combination with nivolumab or pembrolizumab (NCT04044859, NCT05601752) hoping to replicate this efficacy across multiple solid cancers are in progress.

In TCR-engineered cell therapies, T cells are genetically modified to express novel TCRs that target specific tumor peptides. Peptides must be processed and presented by major histocompatibility complex (MHC) molecules for immune recognition by TCR-engineered T cells to occur [9]. Thus, unlike CAR-T cells which are MHC independent and can only target cell surface tumor antigens, TCR-T cells can be engineered to recognize intracellular antigens present within the tumor tissues making them an attractive option for solid tumors. However, this MHC dependency is a major limitation to broader application as it restricts antigen recognition to the specific MHC allele presenting the epitope. Patients receiving TCR T cells are also at risk of cytokine release syndrome, and off-target toxicities due to recognition of tumor antigens on healthy tissues.

This is clearly a significant stride for the field, but we have a long way to go before these therapies become routine in clinical care for solid tumors. TIL and TCR-engineered therapies share most of the challenges associated with adoptive cellular therapies which hamper their broad application and accessibility such as complex labor-intensive manufacturing processes as well as prohibitive cost of final product. With AMTAGVI and TECELRA currently listed at $515,000 and $727,000 respectively and production lasting anywhere from 14 to 34 days [10, 11], the future lies in continuous technological innovation to address manufacturing complexities and produce scalable therapies that are more cost-effective.

Looking ahead, as researchers continue to explore innovative approaches to enhance therapy effectiveness and better outcomes, there is a need to balance innovation and accessibility to ensure equitable access for all patients.

References

1. ISCT Global Regulatory Report - International Society for Cell & Gene Therapy
2. February 15, 2024 Summary Basis for Regulatory Action - AMTAGVI
3. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. Journal for ImmunoTherapy of Cancer. 2022;10:e005755. doi:10.1136/jitc-2022-005755.
4. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313(23):1485-1492. doi:10.1056/NEJM198512053132327.
5. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318-1321. doi:10.1126/science.3489291.
6. Allison BW, Pippa GC, Omid H. Tumor-Infiltrating Lymphocyte Therapy in Melanoma: Facts to the Future. Clin Cancer Res. 2023;29(10):1835-1854. doi:10.1158/1078-0432.CCR-22-1922.
7. August 1, 2024 Summary Basis for Regulatory Action - TECELRA
8. D'Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet. 2024;403(10435):1460-1471. doi:10.1016/S0140-6736(24)00319-2.
9. Schendel DJ. Evolution by innovation as a driving force to improve TCR-T therapies. Front Oncol. 2023;13:1216829. doi:10.3389/fonc.2023.1216829.
10. FDA approves first T-cell therapy for a solid tumor
11. FDA signs off on first engineered cell therapy for a solid tumor