Preclinical development of a T cell product tunable by soluble factors for melanoma and glioblastoma patients refractory to prior intratumoral immunotherapy.

Immunotherapy that involves the blockade of immune checkpoint molecules at the surface of immune- and cancer cells results in long-lasting responses in a subgroup of patients with a variety of cancer types. Vast clinical efforts have been dedicated to advancing treatment with PD-(L)1 and CTLA-4 immune checkpoint
blocking antibodies. Unfortunately, most solid tumors are refractory to these therapeutics, and the mechanisms of resistance require elucidation to develop new effective complementary strategies of cancer immunotherapy. In
our ongoing phase I/II clinical immunotherapy trials with intratumoral immunotherapy (including autologous myeloid dendritic cells) we documented an influx of immune cells (dominated by T cells) in regressing and also in some of the resistant metastatic lesions of melanoma patients and in the CSF of GBM
patients. Well documented cases of “Mixed” responses (: at the same time response and progression of different metastases in the same patient) indicated that in order to achieve a complete response, the TILs are either too few in numbers or lack sufficient functional capacities at specific metastatic sites. Given the proven anti-tumor phenotype of these T cells (capable of eradicating some of the metastases), we hypothesize that they could be used as a starting material to develop an adoptive T-cell therapy and/or generation of a CAR modified TIL product and as such lead to new forms of adoptive cellular immunotherapies
potentially rescuing melanoma and GBM patients in whom we can successfully induce an anti-tumor immune response but that need this extra level of activity to achieve a durable complete response.