Project 2. There have been major advances in recent years enhancing our understanding of the immune response to cancer in general and lymphoma in particular. These advances have impacted on clinical care. The SPORE has a long-standing interest in exploring the unique aspects of the lymphoma microenvironment and how cross-talk between malignant lymphocytes and benign cells contributes to both tumor growth and immunosuppression. SPORE investigators have also explored novel approaches to modifying that microenvironment in a way that enhances antigen presentation and development of an anti- lymphoma T cell response. T-cell checkpoint blockade is creating great excitement in the overall field of cancer immunotherapy but early phase studies indicate it has suboptimal efficacy as a single agent in non-Hodgkin lymphoma (NHL). Based on this background, the underlying hypothesis of Project 2 is that modifying the lymphoma microenvironment to augment antigen release, uptake and presentation, will increase the lymphoma T cell response and enhance the efficacy anti-PD1 therapy of NHL. We will assess this hypothesis by exploring two specific aims. In the first aim, we will conduct parallel clinical trials combining anti-PD1 therapy with in situ immunization based on intratumoral manipulation of the NHL microenvironment using two distinct strategies. The first strategy involves enhancing antigen release and uptake through node cryoablation followed by intratumoral injection of autologous dendritic cells (DCs). The second strategy involves enhancing antigen presentation and T cell activation through intratumoral injection of virus-like particles (VLPs) containing a Toll Like Receptor 9 (TLR9) agonist. In the second aim, we will evaluate the immune response to these treatments, with a focus on the systemic and intratumoral T cell response. Additional clinical and correlative studies will be designed based on lessons learned from the first set of clinical trials and correlative science. Overall, this project will provide critical information on whether local modification of the microenvironment can enhance the overall systemic immune response and therapeutic efficacy of anti-PD1 therapy, and what approach is best to achieve that goal.
Project 2 Growing evidence suggests development of a robust anti-tumor immune response can be enhanced by modifying the tumor microenvironment in a manner that enhances release, uptake and presentation of tumor antigens to T cells. This project will explore two distinct strategies of tumor microenvironment modulation combined with checkpoint inhibitor to enhance anti-lymphoma response. The first involves intra-tumoral injection of autologous dendric cells into a cryoablated tumor; the second involves injection of a tumor with a virus-like particle containing immunostimulatory DNA.
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