SP 4

Tumor-reactive T-cells and response to immune checkpoint blockers

Just a few years ago the median survival of patients with melanoma who have distant metastases was less than 1 year. Tumors can avoid immune surveillance by stimulating immune inhibitory receptors that function to turn off established immune responses. Hence, therapeutic inhibition of these so called immune checkpoint blockers is a potential method to boost anti-tumor immunity. With ipilimumab as the first developed immune checkpoint blocker a significant impact on survival of patients with distant metastatic disease was achieved with the potential to lead to long-term survival. For an effective immune response against the tumor tumor infiltrating lymphocytes (TILs) seem to be crucial. In melanoma, higher TIL infiltration of primary melanoma could be associated with a better prognosis. In addition in vitro expanded TILs can be used therapeutically after a lymphodepleting chemotherapy to induce a tumor response. However, till today not much is known about the TIL repertoire that leads to tumor regression. In addition, there are hints that TILs are important to elicit a tumor response in the treatment with immune checkpoint blockers.
We plan therefore to characterize the TIL infiltrates of melanoma metastases before and after start of treatment with immune checkpoint blockers like ipilimumab and PD-1 antibodies to find better markers for treatment response and get more insights in TIL which are able to induce melanoma regression.

The following aspects will be investigated:

• 1. Immunohistochemical analysis of TIL before and under treatment with immune checkpoint blockers to describe density and subsets which lead to a clinical response using a high-resolution automated microscopy on complete tissue sections

• 2. Characterisation of TIL repertoire in the tumor compared to peripheral blood by deep-sequencing of the TCR repertoire before and under treatment with immune checkpoint blockers.

• 3. Extract and expand TIL from melanoma metastases of patients before and under treatment with immune checkpoint blockers to define antigens recognized by the clones dominant in the TIL population and find potential differences after initiation of treatment with immune checkpoint blockers.

These studies not only should help to find biomarkers for response but are crucial to find out if TIL treatment and treatment with immune checkpoint blockers might be a useful combination - to eventually plan a phase 1 trial of this combination treatment.

Keywords: melanoma, TIL, immune checkpoint blocker, ipilimumab, PD-1 antibody