CAR T cell therapies are limited by T cell exhaustion and poor CAR T persistence, which result in suboptimal antitumor activity in patients. Transcription factors govern these processes, and thus, have emerged as ideal targets for enhancing CAR T cell potency. My talk will introduce a conceptual framework for how T cell fitness impacts CAR T cell efficacy and describe transcription factor engineering approaches for enhancing CAR T cell fitness.

Loss or downregulation of the target antigen has emerged as a major mechanism of resistance to CAR T cells. Conventional CAR T cells are susceptible to immune escape because they require high target antigen density for activation. By engineering intracellular signaling, we have developed a novel platform that amplifies the CAR T cell response to low antigen density, enabling the targeting of tumors with heterogeneous antigen expression.

This talk will present research on response and toxicity correlates in chimeric antigen receptor (CAR) T cell therapy for large B cell lymphoma (LBCL). It will discuss CAR T regulatory cells and a novel subset of tumor-associated macrophages as emerging mechanisms of resistance to CD19-CAR T cell therapy in LBCL, and will conclude with unpublished work on modeling these resistance mechanisms and CAR T cell designs to overcome resistance.

Tumor heterogeneity is a major obstacle to effective cancer therapy. To overcome this issue, we developed a T cell engineering strategy that promotes in vivo  persistence and catalyzes a multicellular antitumor immune response, providing enhanced eradication of hematological and solid tumors.

Autologous CAR T cell manufacturing is costly and complex, leading to delays in treatment and barriers to access. Allogeneic cell products from a healthy donor or a pluripotent stem cell are readily available ‘off-the-shelf,’ but limited by host immune rejection. I will describe our recently developed approaches to host immune evasion based on 1) manipulating cell adhesion and 2) using viral immune evasins.

Autoimmunity, which impacts over 50 million people in the United States, occurs when the immune system mistakenly attacks host tissue. While cell therapies have been transformative for some cancers, application of cell therapies to autoimmune disease has been limited by safety risks, pretreatment chemotherapy, and lengthy inpatient stays. This presentation will share Cartesian’s strategy to overcome these hurdles with RNA, enabling safe and effective treatment of patients with autoimmune disease.

B-cell-depleting chimeric antigen receptor T cell (CAR T) therapy has shown remarkable and durable utility for the treatment of autoimmune diseases. The development of novel advanced CAR T products needs to account for the unique considerations that autoimmune patients have compared to oncology patients. The role of preclinical studies to further evaluate and optimize these advanced CAR T candidates will be discussed.

Allogeneic mesenchymal stromal cells (MSCs) show inconsistent efficacy in immune disorders due to insufficient immunosuppression. We enhanced their function by engineering MSCs with chimeric antigen receptors (CARs). As a proof of concept model, we developed CAR-MSCs targeting E-cadherin to treat graft-versus-host disease and inflammatory bowel diseases. CAR-MSCs improved T-cell suppression and targeted localization, significantly ameliorating symptoms and survival. This method promises a broadly applicable approach to boost immunosuppression in various conditions.

Challenges in the CAR T field include persistence and off-target effects. ArsenalBio is leveraging synthetic biology to enhance both the specificity and potency of CAR T cells. ArsenalBio’s logic-gated technology enables CAR T cells to selectively respond based on the presence of two tumor antigens, and avoid when those antigens appear individually on healthy cells. CAR T cells are also engineered to contain Synthetic Pathway Activators (SPA) and shRNAs that improve persistence and survival in the immunosuppressive tumor microenvironment. ArsenalBio's approach addresses critical barriers to CAR T efficacy and safety in solid tumors, potentially broadening the therapeutic landscape for patients with limited treatment options.

Engineered immune cells, such as CAR T cells, show promise for immuno-oncology but must overcome the obstacle of on-target/off-tumor toxicity. Novel logic-gated strategies, like the Tmod platform, offer promising avenues by recognizing combinatorial antigen profiles. The modular Tmod system integrates an activating CAR with an inhibitory receptor, providing a safety switch to spare normal tissues expressing inhibitory antigens.

Obsidian's cytoDRiVE platform enables pharmacologic regulation of protein expression using drug-responsive domains (DRD). Our lead clinical candidate, OBX-115, in Phase 1/2 clinical development (NCT06060613), is an IL2-free tumor infiltrating lymphocyte (TIL) cell therapy product using regulatable membrane-bound IL15 to drive IL2-independent TIL persistence and efficacy. Preclinically, we are coregulating two cytokines, evaluating novel DRDs, and pairing DRD regulation with inducible promoters to enable spatiotemporal control of protein expression. These technologies have the potential to unlock the therapeutic window of cell therapies armored with potent inflammatory mediators, such as IL12 and LIGHT, to remodel the microenvironment of cold and fibrotic tumors.

CAR T cells have transformed cancer treatment, yet only a small fraction of cancer patients benefit from these therapies. The knowledge of tumor-specific targets is the rate-limiting step in developing new CAR therapies. Conventional CARs target membrane proteins, few of which are specific to tumors. We will discuss new methods for uncovering tumor drivers presented by HLA and novel methods for overcoming the challenges of targeting pHLA using CARs.