Session

04.02.2019     14:30–16:00

Title:
Workshop 1: Immunotherapy Screenings and Biomarker
Type:
Workshop Sessions

04.02.2019
14:30–16:00

Title:
Workshop 1: Immunotherapy Screenings and Biomarker
Type:
Workshop Sessions


14:30–15:15
Part 1: Predominance of terminally differentiated T cells among tumor infiltrating lymphocytes impair response to PD-1/PD-L1 inhibition in Merkel cell carcinoma
Jürgen Becker (Essen)


15:15–16:00
Part 2: Immunotherapy for gastrointestinal solid tumors
Niels Halama (Heidelberg)


Predominance of terminally differentiated T cells among tumor infiltrating lymphocytes impair response to PD-1/PD-L1 inhibition in Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, highly malignant skin cancer known for its high rate of metastasis and disease-related death. Recently, PD-1/PD-L1 checkpoint inhibition was recognized as an efficient treatment option for hitherto poorly manageable advanced metastatic patients. However, a significant proportion of patients demonstrate primary treatment resistance, and predictive biomarkers of treatment response are not established. The present study is an explorative analysis of baseline clinical and molecular biomarkers of response to anti-PD-1/PD-L1 therapy in MCC. 41 patients with advanced metastatic MCC were treated with the PD-1/PD-L1 blocking antibodies avelumab (n=14), nivolumab (n=10), or pembrolizumab (n=17) at three clinical centers. The clinical parameters male gender, primary localisation on the extremities or trunk, no previous immunosuppression, and unimpaired overall performance status were associated with a favourable treatment response. Age, laterality of primary, site of metastasis, preceding chemo- or radiotherapy, and type of therapeutic antibody showed no response association. Previously suggested molecular biomarkers from tumor tissue (PD-L1, Merkel cell polyomavirus) and blood (LDH, CRP, neutrophil/lymphocyte ratio) determined at therapy baseline were also not associated with treatment response. A molecular immune profiling of baseline tumor tissue in n=15 patients revealed a high density of tumor-infiltrating CD8+ T cells and CD68+ macrophages in patients responding to PD-1/PD-L1 blockade. However, intratumoral frequencies of CD4+ T cells and FoxP3+ regulatory T cells showed no association with response. In contrast, baseline tumor tissues from responders revealed a lower T-cell clonality, but a higher T-cell receptor diversity as compared to non-responders. Moreover, tumor tissue from responders demonstrated a high expression of genes involved in T-cell activation and cytolytic function, and contained a T-cell infiltrate enriched by central memory T cells, whereas in non-responders, this infiltrate was predominated by terminally differentiated effector T cells. This explorative study identified a variety of new clinical and molecular baseline characteristics associated with response to anti-PD-1/PD-L1 therapy in MCC, which demand further evaluation as predictive markers in large patient cohorts.

Immunotherapy for gastrointestinal solid tumors

Gastrointestinal solid tumors are still not among the cancer entities showing promising results from immunotherapy. While for skin and lung cancer immunotherapy has already reached standard-of-care level, it has not reached this Level for colorectal, pancreatic or gastric cancer. Few exceptions exist (e.g. microsatellite instability), but the question remains open why the gastrointestinal solid Tumors are resistant to immunological interventions. The complexities of the specific immunological microenvironments form the basis for the insufficient efficacy and the details of quantities and localizations of immune cell subsets form an important component in developing new therapeutical strategies. Clinical strategies beyond classical adaptive immunity activation (i.e. checkpoint inhibition) present new potential avenues for these cancer entities.