Rubius Therapeutics is developing an entirely new class of allogeneic cellular medicines by culturing and genetically engineering red blood cells to treat cancer. RTX-240, currently in a Phase 1 clinical trial for treatment of solid tumors, is an allogeneic cellular therapy product candidate engineered to replicate the human immune system by broadly stimulating the adaptive and innate immune systems to generate an immune response. RTX-240 expresses 4-1BBL and IL-15TP, a fusion of IL-15 and IL-15 receptor alpha, on the cell surface with the goal of improving anti-tumor activity and overcoming resistance to immunotherapy in patients with solid tumors. RTX-240 is currently being explored as monotherapy in solid tumors, is expected to be evaluated in relapsed/refractory acute myeloid leukemia, and, in the future, in various immune-oncology combination studies.

By harnessing the full T cell receptor complex independent of HLA matching, TRuCs are a promising new approach which could improve upon the safety and efficacy of marketed CD19 therapies and benefit solid tumor patients, an area CAR T therapies have largely failed. We will also discuss the expanding pipeline by utilizing versatile TRuC platform to address some of the primary challenges to cell therapies such as the hostile and immunosuppressive tumor microenvironment.

Our 3T-TRACE platform identifies TCR-target pairs in an unbiased and comprehensive manner. By selecting clonally enriched TCRs from TILs from cancer patients responding to checkpoint inhibitor treatment, we have identified a portfolio of novel and widely shared targets, many of them belonging to the class of cancer/testis antigens (CTA), which are tumor-specific and lack normal tissue expression. We will update on the progress made developing therapeutic programs targeting the novel targets identified.

Triumvira develops T cell therapies engineered with the proprietary T cell antigen coupler (TAC) receptor. TAC is designed to redirect T cells to tumor cells and to activate T cells by co-opting the endogenous T cell receptor complex independently of MHC, leading to safe and effective tumor rejection in mouse models. Triumvira previously cleared an IND/CTA submission for TAC01-CD19 in LBCL and proceeds with a second solid tumor program currently in preclinical development.

This talk will introduce CAR engineered macrophages as a novel cellular immunotherapy and describe how they have the potential to overcome solid tumor challenges.

Recently, there have been major advances in defining tumor-reactive T cells within human maligancies. Our group has published that the tumor-reactive CD8 T cells are highly enriched in the CD39/CD103 double positive (DP) fraction of cells. These cells are found in most solid malignancies that we have explored thus far, including melanoma, lung cancer, renal cancer, breast cancer, head and neck cancer, colon cancer, ovarian cancer, and pancreatic cancer. Interestingly, some cancers show a much higher frequency of these CD39/103 DP CD8 TIL (e.g., melanoma and lung cancer 30-80%), while other tumor types have a much lower frequency of these cells (e.g., pancreatic and colorectal liver metastases 2-15%). The CD39/103 DP CD8 TIL have a resident memory phenotype, and are highly enriched within tumor site when compared to peripheral blood. These cells are enriched for cells reactive to tumor-mutated Ags and viral-associated tumor Ags (HPV cancers). They express high levels of exhaustion markers: PD-1, CTLA-4, TIM-3, Lag-3; but also are enriched for activation and proliferation markers (e.g., 4-1BB, Granzyme B, and Ki-67). More recently, we have found a way to grow these cells in culture with the ultimate goal of delivering a TIL population that is highly enriched for tumor reactivity. To this end, we have found that we can sort and culture as few as 2000-10,000 DP CD8 TIL and grow them to billions in a 5-week span. We plan to perform a Phase I clinical trial with the expanded DP CD8 TIL population within the coming year.

CAR T cell therapy is currently approved in relapsing or refractory B-ALL and DLBCL. In this presentation, we describe the three categories of CAR treatment resistance of first-in-class, genetically engineered T cells, related to: 1) product T cell fitness and dose of specialized cells; 2) tumor microenvironnment; and 3) target evasion. This information informs on product and treatment optimizations, and next-generation immunotherapies.

Immune cell therapeutics, including autologous CAR-T cells, have gained popularity based on the remarkable response rates in patients with B cell malignancies. The promise of off-the-shelf CAR-T cell therapies necessitates gene editing technology to safely deploy T cells derived from healthy donors and to promote their persistence. A next-generation, CRISPR hybrid RNA-DNA (chRDNA) technology, with significantly enhanced editing specificity for the generation of allogeneic CAR-T cell therapies, will be discussed.

PACT is developing personalized adoptive cell therapy consisting of neo-epitope targeted T cells. T cells recognizing cancer neoepitopes are isolated from patient PBMCs using a sensitive microfluidic nanoparticle system. Neoepitope specific TCRs are engineered into fresh CD8 and CD4 cells using non-viral genome engineering. Following minimal expansion ex vivo, the engineered cells are re-infused. My presentation will describe the upstream product selection process and the ongoing Phase 1 clinical study.

Vγ9Vδ2-T cells constitute the majority of the γδ T cells present in blood. They have a natural trophism towards tumors and their presence in tumor infiltrating lymphocytes correlates well with prognosis across a wide variety of different indications. Vγ9Vδ2-T cells constitute a potent cytotoxic immune effector cell population that can be (locally) activated and redirected to tumor cells using bispecific antibodies. Our recent preclinical data support the notion that this may yield a potent, yet safe cancer treatment modality. The latest progress in the preclinical development of our lead molecules will be discussed.