Adoptive Cell Therapy with Tumor Infiltrating Lymphocytes: Clinical Results and Correlation to Clinical Success

The presence of immune cells in the tumor microenvironment, in particular T cells, strongly correlates with favorable clinical outcome. Adoptive cell transfer (ACT) of ex vivo expanded Tumor Infiltrating Lymphocytes (TIL) followed by tumor microenvironment preconditioning, is an effective treatment for metastatic melanoma, as demonstrated by multiple cancer centers. Over 100 patients were treated at our institute and about 40% experienced objective responses, including 12% complete remissions. The therapy was also effective in patients who were refractory to immune checkpoint inhibitors.

Searching for parameters of clinical response, we examined a 21 different cytokines in the serum of patients and in their melanoma and TIL cultures. In addition, we analyzed TIL infusion products in order to define specific phenotypic T-cell subsets which correlate to tumor regression. Using bioinformatical tools, we evaluated 600 subpopulations. Cytotoxic T cell, co-expressing CD28 and CD33 were positively correlated to clinical response. By FASC sorting or genetic engineering, we were able to enrich CD8⁺CD28⁺CD33⁺ cells with superior in vitro and in vivo activity in comparison to their CD8⁺ counterparts. Enrichment of this specific T cells subset by rational manipulation or selection may further improve the clinical response to TIL-ACT. Using new multi-marker cytometry by Time-Of-Flight (CyTOF) enables the measurement of 39 extra- and intra-cellular expression markers simultaneously for rapid and robust identification of new cell populations of interest. This may significantly enable efficient anti-tumor reactive T cell selection to improve the clinical outcome of patients treated with TIL-ACT.