• 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

CAR T cells have shown remarkable efficacy in patients with B-cell malignancies but extending this therapy to other hematologic cancers remains challenging. I will summarize results of our latest efforts in developing engineered T cell therapies against non-B cell leukemia and lymphoma and evaluating these approaches in Phase I clinical trials.

This talk will feature novel mechanisms of resistance to CAR T therapy, novel target antigens and CAR T cell products for treating multiple myeloma, virus-free transposon-based gene-transfer for CAR T manufacturing, and a novel application for CAR T in fungal infections.

CAR T therapy is changing the treatment paradigm for lymphoid malignancies. However, there are still significant challenges to be overcome as the majority of patients will eventually fail this therapy. Moreover, CAR T therapy is still not working satisfactorily in most cancer types. Dr. Ruella will provide an overview of the latest findings of his group on resistance mechanisms to CAR T immunotherapy and strategies to overcome them.

To date, clinical trials with CAR T cells have had limited efficacy in patients with solid tumors. To improve patient outcomes, we have specifically explored human cancer immune context and revealed immune suppression pathways. We have then engineered human CAR T cells to address these immuno-suppressive pathways to maintain CAR T cell effector function and persistence in the tumor microenvironment.

This presentation will discuss advancing the CAR T field from autologous to allogeneic approaches; TALEN: gene-editing platform to optimize persistence, potency, and safety of CAR T; and broadening success of allogeneic CAR T therapies from hematologic malignancies to solid tumors.

Clonal master iPSC lines can be used as a renewable source for repeatedly and cost-effectively manufacturing cell therapy products that can be delivered off-the-shelf to treat many patients. Our cells of interest are the cells of the immune system. And our cell therapy product candidate pipeline is comprised of immuno-oncology programs, including off-the-shelf NK- and T cell product candidates, that target a broad range of liquid and solid tumors.

Cancer immunotherapy has demonstrated robust efficacy but still faces significant challenges when treating solid tumors. To potentially overcome major challenges, we have developed a synthetic cancer-targeting gene circuit platform that enables a tumor-localized combinatorial immunotherapy: a Trojan horse-like approach. Once the circuits enter cells, they will sense the activity of several cancer-associated transcription factors, and get activated in cancer cells, while potentially keeping normal cells unharmed. The circuits trigger robust therapeutic efficacy in vivo in ovarian cancer mouse models. This platform can be adjusted to treat multiple cancer types and can potentially trigger any genetically-encodable immunomodulators as therapeutic outputs.

Data will be presented that demonstrates a PBMC humanized mouse platform can be used to de-risk therapeutic antibody and cell-based preclinical drug development. The assay is fast, sensitive, reliable, reproducible and allows a holistic approach to drug discovery where, in one platform, you can simultaneously evaluate efficacy, cytokine induction, immunophenotyping, mouse clinical evaluation and downstream organ toxicity. 

We have established new manufacturing and quality control processes to produce a recombinant CRISPR/Cas9 protein that is suitable as an ancillary material for cell and gene therapy applications. Here we demonstrate the use of this newly manufactured Cas9 protein under our Cell Therapy Systems “CTS” brand – CTS TrueCut Cas9 Protein – as benchmarked against our catalog Cas9 product in primary T cells with both the bench scale Neon and newly released large scale CTS Xenon electroporation system.

Dual-targeted Fine-tuned Immune Restoring (DFIR) CARcT cells have been designed for CURE of ccRCC. Increased efficacy is achieved through dual-targeting CAR which allows their activation in the presence of either antigen to mitigate against solid tumor heterogeneity. Elevated safety is addressed through fine-tuned CARs which have affinities of the scFv targeting moieties tailored to only recognize high-density tumor-associated antigens (TAAs). Immune restoration is attained through delivery of checkpoint blockade inhibitor antibody payloads that act locally on the tumor microenvironment, not only to prevent CAR T cell exhaustion but also to restore anti-tumor activity of the educated tumor infiltrated lymphocytes. 

Cell therapy in solid tumors has to address the challenges of heterogeneity of tumor-specific neoantigen expression, ability to traffic to the tumor, and overcome the hostile tumor microenvironment. Investigational tumor infiltrating lymphocytes (TIL) cell therapy, an autologous patient-specific polyclonal cell therapy, is being studied in multiple tumor types where there is an unmet need. Iovance is developing TIL cell therapies with the lead indication in advanced or metastatic melanoma.

Minerva Biotechnologies is focused on cancer and stem cell therapeutics. We are developing cancer immunotherapies targeting 80% of solid tumors and to prevent cancer metastasis.

The paucity of tumor-specific antigens is a challenge for all targeted therapies, most are simply overexpressed tumor-associated antigens. Affinity tuning CAR T cells provides both selectivity to tumor cells overexpressing a tumor-associated antigen to reduce on-target/off-tumor toxicity and enhances CAR T cell activity in animal models. We have initiated a Phase I trial of an affinity tuned CAR T cell that also can be tracked in real time in patients.