PD-1 antibodies are transformative in cancer therapeutics. They have shown significant anticancer activity as monotherapy across a large number of major cancer types and across lines of therapy. Precision medicine tools have enabled trial enrichment and patient segmentation. They have also provided insights to potential resistance biology and enabled informed combination selection. PD-1-based combination therapies are also showing promise broadly across tumors and lines of therapy.

Clinical combination studies including PD-1 checkpoint inhibitors exploded in the 7 years since the first PD-1 checkpoint inhibitor approvals. Expectations of combination success were high at first. Seven years on, it is important to assess these studies more realistically. The presenter recently published a cross sectional study of PD-1 pathway checkpoint inhibitor clinical trials. Encouraging and discouraging results will be reviewed to guide thinking about future combination strategies.

In a single-institution cohort, long-term outcomes were assessed after discontinuation of anti-PD-1 for advanced melanoma (n=396). Of 102 complete responders, the probability of relapse was 27% at 3 years. No association was seen between treatment duration and relapse risk. Among patients treated with anti-PD-1 who were re-treated after relapse, response was observed in 15% (of 34) patients re-treated with anti-PD-1 and 25% (of 44) patients re-treated with ipilimumab + anti-PD-1.

The success of early cancer immunotherapies has led to the development of novel therapeutic approaches including T-cell engagers. T-cell engagers are typically multi-specific antibodies directed against the T-cell and one or multiple tumor-associated antigen (TAA), whose therapeutic strategy is to 1) engage T-cells, 2) activate the T-cells and 3) engage tumor cells and thus induce tumor cell killing. Preclinical evaluations rely on the development of humanized models that mirror key properties of human settings to assess the therapeutic potential of multi-specific biologics.

Based on our platform of primary patient-derived 3D microtumor (PDM) co-culture models with autologous immune cells (TILs or from PBMCs), we perform efficacy testing studies on compounds, immunotherapies and combination treatments. We will present recent data on PDM models from various tumor entities, including functional data and in-depth cell signaling pathway activity analyses from highly multiplexed total and phospho protein profiling data.

The identification of new targets and preclinical evaluation of existing and new targets is critically important for the prioritization of which agents should move forward for testing in clinical trials. This process has not been optimal for the identification of effective immune-oncology therapies. New approaches to target identification and preclinical testing using animal models and new ex vivo immune-oncology models will be discussed.

B cells in human cancer have recently come into vogue as important contributors to the anti-tumor immune response in cancer patients. Specifically, B cells and the immune structures in which they reside (tertiary lymphoid structures) correlate with increased survival and immunotherapeutic response for several solid tumor types. Our research is focused on linking anti-tumor function of the B cells with their location and phenotype utilizing high-level immunological techniques.

Adoptive T cell therapies and, in particular, chimeric antigen receptor T cells (CAR T) are leading to significant responses in cancer patients, in particular B cell leukemias and lymphomas. However, a significant subset of patients still does not respond or eventually relapses after this therapy. In his talk, Dr. Ruella will highlight recent findings in the pathogenesis of relapse after CART-19 and discuss novel therapeutic approaches aimed to increase CAR T feasibility and efficacy.

Current animal models used in pre-clinical testing are limited. Learn about the new developments in humanized animal models to get ideas on how models can be applied to solve specific translational challenges. Included is an overview of how models mimic human immunity in the context of immunotherapy and therapeutic targets.