Purpose: Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs), a type of cancer immunotherapy, has demonstrated promising results in patients with advanced cancer with cases of complete responses even after checkpoint blockade immunotherapy (CBI). However, only 40% of melanoma patients respond to ACT and the inconsistency of clinical response stresses the need for a finer understanding of the underlying mechanisms.
Experimental design: To understand the contribution of the antigenic or antitumoral reactivity, we interrogated cell products from two melanoma patients treated with TIL-ACT. Annotated clones were then tracked in longitudinal samples to understand the dynamics of tumor-reactive TILs. To this end, cell products were sequenced, screened with private peptides and interrogated against autologous tumors.
Results: The responder’s ACT product (ACTP) was enriched in tumor-reactive fraction, translating to a higher absolute number of tumor-reactive cells infused in this patient. Also, the number of recognized immunogenic epitopes was higher for this patient. Neoantigen-specific clones showed stronger responses than tumor-associated-antigen (TAA)-specific counterparts. The T-cell receptor (TCR) repertoire was highly influenced by the expansion phase of the ACTP. TILs persistence in the blood as well as tumor infiltration post TIL-ACT were more ambiguous in their dynamics, despite a trend for an association between clinical benefit and tumor-infiltration and blood persistence of identified tumor- reactive clonotypes.
Conclusion: In this small study, we could validate immune correlates of TIL-ACT efficacy with the characterization of ACT product specificity. The extensive study on the thirteen available patients would allow to deepen the knowledge on the dynamics of tumor-reactive and antigen-specific clonotypes, dissecting their blood persistence and tumor infiltration potential and association with clinical response.