Chemotherapy reduces tumor mass, increases vascular permeability, disrupts immunosuppressive networks, and upregulates expression of stress induced NKg2DL, while also depleting immune effector cells. We have genetically modified γδ T cells, which broadly recognize tumor stress signals to function in therapeutic concentrations of specific chemotherapy agents enabling delivery at the time when the tumor is at highest vulnerability. We are currently evaluating this approach in ongoing preclinical models and clinical trials.

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Within cell therapy development the use of in vivo animal models can present significant hurdles in translatability to humans. As a result, the establishment of complementary high-quality in vitro efficacy and safety studies to foster the development of such therapies has become critical before filing for Investigational New Drug (IND) status.  Charles River has developed an in vitro efficacy package aimed at determining cell therapy activity, specificity and potency.

CD8+ CTL-based therapies, including CD19-targeted CAR T cell therapy, have seen substantial limitations in B cell malignancies, producing durable remissions only in less than one-half of treated patients; relapses result primarily from the target epitope loss or poor in vivo persistence of the CD8+ T cells. To overcome these limitations, we develop a novel form of immunotherapy for B cell malignancies using multi-specific CD4+ CTLs with superior ability for in vivo persistence. Here, we present results from preclinical and translational studies.

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Despite advances in immunoncology, many patients fail to respond to CPI. High Treg counts correlate with poor prognosis to CPI. RG6292 is an ADCC/ADCP competent monoclonal antibody (human IgG1) with an afucosylated Fc region binding with low affinity but high avidity to CD25. RG6292 preferentially depletes CD25++ Tregs over CD25+/- activated CTLs. RG6292 preserves IL-2 signaling to allow effective anti-tumor responses. Preclinically, RG6292 promoted eradication of established tumors and synergized with CPI. RG6292 provides a novel therapeutic approach to alleviate one mechanism of immune suppression in the tumor microenvironment. Clinical testing is currently ongoing in patients with advanced solid tumors (NCT04158583).

g9d2 T cells display potent anti-tumor activity and infiltrate into solid and hematologic tumors and are associated with a positive clinical prognosis. ICT01, a novel cancer immunotherapeutic mAb targeting BTN3A and activating g9d2 T cells is in clinical stage development. As an approach to potentiate g9d2 T cell-mediated cancer immunotherapy, we characterized the safety and pharmacodynamic activity (i.e., number of g9d2 T-cells) of ICT01 combined with IL-2 (Proleukin) in non-human primates.

The evolving field of NK cellular immunotherapy is modifying what has been learned from T cell gene editing to apply knowledge to NK cell manipulation. Gamida-Cell utilizes transient intracellular delivery of mRNA by electroporation, enabling efficient delivery of immunological adjuvants, cytokines, and CAR constructs into Nicotinamide (NAM)-expanded, allogeneic NK cell. This technique can be easily applied to generate improved off-the-shelf NK cancer therapeutics. mRNA Engineering of NK cells allows for manipulations that have the potential in clinical applications, which would benefit from a higher level of expression for a transient period to all for maximum safety.

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Natural Killer (NK) cells are innate immune cells that can eliminate target cells in an antigen-independent fashion. NK cells can be engineered to express chimeric antigen receptors (CARs), expanded under different conditions, and gene edited to further enhance cytotoxicity, selectivity, and persistence. Nkarta is developing off-the-shelf CAR NK cells to maximize the therapeutic potential of allogeneic NK cells alone or in combination with other agents. 

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Multi-specific antibodies have the unique ability to elicit an immune response at the site of a tumor. By minimizing the toxicities associated with a systemic immune response, tumor-targeted, immune agonist antibodies can increase the therapeutic index for new immune-activating cancer therapies. In summary, we have created multiple platforms for tunable immune activation at the site of the tumor that work with a variety of tumor antigens.

High-affinity IL-2/IL-15Rbg agonist SOT101 (CYT101, RLI-15) as a monotherapy or in combination with pembrolizumab increases immune cell infiltration in tumors in clinically responsive patients in Phase clinical I study (NCT04234113) which is accompanied by NK and CD8+ T cell cytotoxicity, proinflammatory chemokine and IFN-g signaling gene signatures. All patients showed dose-dependent pharmacodynamic responses in blood; however, SOT101 activity in the tumor microenvironment might be pivotal for the therapeutic success.

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Heterogenous target antigen expression and immunosuppression in solid tumors impede clinical implementation of CAR Ts. We armed CAR Ts to secrete a pluripotent proinflammatory neutrophil-activating protein (NAP) from Helicobacter pylori upon target antigen recognition. CAR(NAP) Ts were more successful in reducing tumor growth and enhancing survival of mice than conventional CAR Ts. NAP secretion created an immunologically hot tumor microenvironment supporting DC maturation and bystander immunity with infiltration of CD8+ T cells targeting tumor-associated antigens other than the CAR target antigen. The effect was independent of tumor model and target antigen, indicating broad applicability in various solid tumors and warranting translation into the clinic.

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