Advance-CTR

Advance RI-CTR Pilot Projects Program (Cycle 8)

"The Tumor Microenvironment and Response to Immunotherapies in Follicular and Marginal Zone Lymphoma "

Contact-PI: Ari Pelcovits, MD  | Multi-PI: Adam Olszewski, MD 

The proposed work is important because correlating tumor immune architecture with blood-derived parameters, responses to mosunetuzumab, and somatic mutations will provide novel potential predictors of response or refractoriness to therapy with bispecific antibodies. The hope is to translate this knowledge into immunomodulating therapy to enhance clinical responses to mosunetuzumab Aim #1: Clinic Development: Assess community capacity to develop, implement, and sustain an interdisciplinary patient-centric clinic. Aim #2: Clinic Implementation (trial) to determine the potential reach (i.e., proportion of target population & representativeness), adoption (i.e., the degree to which the intervention can be adopted, implemented, and sustained as intended) and implementation (i.e., resource and staffing costs) of the newly developed clinic intervention. Aim #3: Evaluate inclusion and health equity of EMPOWER PD participants

The objective of the proposed research is to investigate specific microenvironment features in pre-treatment tumor samples from patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL) treated with first-line mosunetuzumab, a bispecific antibody, using spatial transcriptomics.

The long-term research aim is to investigate the tumor immune microenvironment, determine its impact on response to immunotherapy, and enhance such responses through rationally designed immunomodulation.

As a critical knowledge gap, there are no biomarkers to predict response or refractoriness to therapy with bispecific antibodies. Studies in aggressive lymphomas suggest that tumor immune microenvironment may correlate with responses or toxicities (cytokine release syndrome) of immune cell-engaging therapies

The hypothesis is that that specific immune tumor microenvironment features (potentially shared by FL and MZL despite their differing histology) will be associated with a higher chance of response to mosunetuzumab.

The first aim is to investigate specific microenvironment features in pre-treatment tumor samples from patients with FL and MZL treated with first-line mosunetuzumab using spatial transcriptomics, correlate them with peripheral blood immune cell profiles, cytokine profiles in plasma, and response or refractoriness to therapy. The second aim is to examine expression of markers of immune activation and exhaustion as determined by spatial transcriptomics according to specific somatic DNA mutations in FL and MZL tumors samples.

The plan is to address this hypothesis and the aims through spatial gene expression and DNA sequencing. Through a translational collaboration between co-PIs Visium Spatial Gene Expression will be applied, a spatial transcriptome platform, and Oncopanel, a sequencing technology, to formalin-fixed, paraffin-embedded pre-treatment biopsies from 16 patients on clinical trial with mosunetuzumab. Tumor and microenvironment features, including immune checkpoint molecules, T-cell subset analysis, expression of activation and immune exhaustion markers, and architectural features like cell clustering or proximity to malignant B-cells, will be explored to correlate features with response to mosunetuzumab (aim 1) and specific mutation profiles (aim 2).