Aleta’s CAR T Engagers (CTEs) address critical issues in cell therapy, including target antigen density and loss, CAR T persistence and fitness, and immunosuppression. Each program presents a bespoke solution for specific clinical needs: relapses in lymphoma and MM, dual-antigen targeting in AML and Her2-positive solid tumors, triple antigen targeting for CNS cancers. We will update several of these programs at the conference.

Review of current state of the emerging cellular and gene therapy:

Adoptive CAR T cell therapies have delivered profound clinical responses in patients with haematologic malignancies. The Ph 3 randomized Zuma-7 study in second-line R/R large B cell lymphoma has demonstrated superiority for Axi-cel in comparison to standard of care in event-free survival. This session will review current translational findings for Axi-cel function in association with product attributes and pre-treatment tumor characteristics.

Cellular and gene therapy is one of the most significant innovations of our modern era as cellular and gene therapies hold the potential of treating and, in certain circumstances, possibly curing illnesses for which there is no existing standard of treatment or for which only symptomatic therapy has previously been offered. For the success of these therapies, we need to address the challenges with clinical application hindering creating an impact. This presentation will review the challenges, and the strategies to address the challenges associated with the research, commercialization, and limitations from the perspective of clinical sites and patient levels. 

• We present data discussing how increased specific avidity, those TCR’s with strongest antigen binding with the lowest background, correlate with improved TCR function in vitro and in vivo.   
• How CAR T and TCR T avidity is significantly more correlative to in vivo outcome than either cytotoxicity assays or IFN-g release. 
• Methods for using cell avidity to screen constructs and more reliably select lead candidates

Our laboratory has developed, optimized, and translated mesothelin-targeted CAR T cell therapy to patients with mesothelioma, and metastatic breast and lung cancers. We further translated strategies to overcome barriers to successfully translating CAR T cell therapy for solid tumors. One such strategy already in clinic is combination immunotherapy of CAR T cells and checkpoint blockade agents or PD1 dominant-negative receptor within the CAR T cell. These preclinical supportive rationales and clinical trial results will be presented.

Mesothelin is shed from cells by the action of proteases that cut close to the membrane. mAb15B6 binds to the protease-sensitive region of mesothelin proximal to the membrane, inhibits mesothelin shedding, and makes a very active CAR T cell that is superior in activity in mouse tumor models to CAR T cells made with mAb SS1 that binds to a distal epitope. mAb 15B6 is humanized and ready for clinical development.

Cellular therapies have led to unprecedented clinical success in hematologic malignancies, but it has been a challenge to replicate this in the solid tumor arena. This presentation will focus on some of the unique challenges in solid tumors, with an emphasis on optimal target selection.

My group has characterized GPC3 as a liver cancer target for antibody and cell based immunotherapies in the past decade. In the present talk, I will discuss our recent research on GPC2 and GPC1 as new tumor targets and engineering of CAR T cells to treat solid tumors such as neuroblastoma and pancreatic cancer. I will also describe new strategies including nanobody technology to improve efficacy of CAR T cells.

Bio4t2 develops advanced Chimeric Antigen Receptor T cell (CAR T) therapies to treat patients with solid tumors. Our differentiated platform for accelerated discovery and development of pharmacologically calibrated CAR Ts that is also amenable to any other immune cell types with therapeutic potential along with our current therapeutics pipeline and next-generation products will be introduced. The preclinical data and the progress toward clinical studies for our first-in-class CAR T therapy against a novel tumor target will be described. Our CAR Ts are optimized to treat patients with a high degree of safety, efficacy and durability for a long-lasting response.

Chimeric antigen receptor (CAR) T cells are remarkably efficient for treating leukemia, but not yet developed for gastrointestinal cancers (GICs) and neuroendocrine tumors (NETs). We discovered a nanobody VHH1 bound NET cells by targeting CDH17, a cell adhesion protein that is also expressed in certain normal epithelial cells. CDH17CAR Ts eliminate GIC and NET tumors, but do not attack the normal cells in multiple preclinical tumor models, as CDH17 is only localized at tight junction between the normal epithelial cells. Thus, CDH17 represents a new class of tumor-associated antigens that are “masked” from being attacked by the CAR Ts in normal tissues.

Chimeric Antigen Receptor (CAR) T cell therapy is a new type of “living drug” that has proven to be a powerful immunotherapy for hematologic malignancies. However, this success has not yet been transferred to solid tumors. My talk will focus on how to translate CAR T cell therapy to solid tumors, especially ccRCC. I will also discuss the application of humanized mouse model in immunotherapy assessment.

T-cell engagers (TCE) have been effective in hematologic cancers but have shown limited efficacy in solid tumors because of on-target, off-tumor toxicities or cytokine release syndrome that limits the therapeutic window for the antibody. We developed a novel TCE using our unique discovery platform which shows selective bivalent antigen binding to target tumor cells overexpressing target antigen while avoiding normal tissues expressing low levels of target.

Autologous T cell therapies have been life-changing for many patients; but virus-specific, allogeneic platforms hold the promise of effective, off-the-shelf treatments manufactured at scale, and delivered to patients within days. In this talk, the flexibility and advantages of EBV T cells and how allogeneic treatments may change the treatment paradigm for cancer and autoimmune diseases will be discussed.

Induced pluripotent stem cells (iPSCs) hold great potential as therapies to repair damaged tissue or replace cell types missing due to genetic defects. However, even iPSCs derived from a patient can mutate in culture, causing immune rejection when they are re-transplanted. Being able to control immune rejection is key to using iPSCs as theraputics. The end goal, for safety and efficiency, is a gene-engineered, hypoimmunogenic, universal cell product.