Programmed and highly targeted activity of cell therapies has the potential to both reduce toxicity and concentrate the therapeutic effect where it is most needed, improving safety and efficacy. Our mission is to engineer and distribute a comprehensive toolkit of clinically optimized technologies for cell-based therapeutics, so we can make an impact across diseases with high unmet needs.

Despite the success with CAR T cells in hematologic malignancies, there are several limitations to this approach including toxicities, CAR T cell exhaustion, and lack of persistence. To overcome the above design limitations of the current generation CAR T constructs, we have generated a next-generation CAR T platform designated Synthetic Immune Receptor (SIR) that provides physiological TCR-like signaling and overcomes most of the limitations of current generation CAR constructs.

Chimeric antigen receptor T cells are genetically modified lymphocytes conventionally re-targeted towards specific macromolecules defined by the variable domains of monoclonal antibodies. Most CAR T cell therapies have been developed to target cell-surface protein antigens; however, antibody-based re-targeting expands the repertoire of macromolecules T cells can target, including carbohydrate-based antigens. Here, we demonstrate that truncated O-glycoforms of tumor-associated antigens are a class of actionable immune targets for CAR T cells.

One of the main barriers to the effective activity of adoptively transferred T cells is their inhibition when they reach the tumor bed. In this study, we discovered that CD5 inhibits CAR T activation and that the knockout (KO) of CD5 using CRISPR-Cas9 enhances the anti-tumor effect of CAR and TCR T cells in multiple hematological and solid cancer models.

NK cell immunotherapy is a promising approach for cancer treatment, with low risk of graft versus host disease and adverse effects. One of the major hurdles of this approach is the immune suppressive tumor-microenvironment. In our work, we applied unbiased large-scale CRISPR screens on both the tumors and the NKs, to identify mechanisms of tumor cell resistance to NKs, for improved NK cell immunotherapies.

One challenge of CAR T cell therapy is tumor relapse due to loss of target antigen on tumor cells or poor persistence of CAR T cells in patients. To overcome this challenge, we have developed CARs that recognize peptide-MHC where the peptides are derived from oncogenic mutations. Arming cytokine-induced memory-like NK cells, which can persist in patients for months, with tumor-specific CARs may lead to better long-term efficacy of CAR-NK cell therapies.

We described human memory-like NK cells with enhanced anti-tumor activity. We have recently demonstrated the safety and promising activity of using memory-like NK cells in AML and MDS. In my talk, I will describe key properties of the memory-like NK cells; summarize the preclinical development of the CAR-armed memory-like NK cells in ovarian and pancreatic cancer, and describe early clinical results and correlative labs from our ongoing clinical trial of cytokine-engineered allogeneic NK cells in combination with CTL4 blockade in patients with advanced head and neck cancer.

• Trends in commercializing cell and gene therapies
• De-centralized versus centralized manufacturing
• Pricing trends, reducing costs
• New trends such as in vivo CAR T delivery

Adoptive cell therapies have demonstrated remarkable outcomes in hematologic malignancies, but efficacy in solid tumors is still lacking. We have established a novel, proprietary monocyte and macrophage-based cell therapy platform based on chimeric antigen receptor macrophages (CAR-M).

This talk will feature novel targets for CAR T therapy that are relevant in several prevalent cancer types, and strategies of advanced CAR T engineering and combination therapy to augment potency and facilitate clinical implementation.  

Allogeneic T cells have qualities that make them an ideal platform for treating disease. Evolution of CAR T designs and next-generation armoring technologies to overcome the hostile tumor microenvironment will be explored, including the promise of a platform that doesn’t require HLA or TCR gene editing and safety, expansion, and persistence implications.

Despite the recent approval of CARVYKTI, historically scFv has been the preferred binding format in CAR T cell therapies. Single domain antibodies (dAb), however, display several favorable biophysical characteristics such as smaller size, increased paratope diversity, and improved stability. Here we compare a set of 20 affinity and domain-matched dAb and scFv-based CARs, evaluate their biophysical properties, and compare their functionality head-to-head to assess which format may prevail.

Major limitations in the CAR field include the poor controllability of CAR T cells after administration in vivo and their limited tumor specificity. To address these important challenges, we have engineered protein-based switches for CAR T cell regulation with an orally available and non-toxic small molecule drug. In addition, we have generated avidity-controlled CARs (AvidCARs) for combinatorial antigen recognition and small molecule-mediated CAR T cell control in vivo.