My laboratory has characterized glypicans including GPC1, GPC2, and GPC3 as immunotherapeutic targets for antibody and cell-based immunotherapies. In this talk, I will discuss our recent research towards the optimization of the extracellular hinge to improve CAR T cells for treating solid tumors such as liver cancer and pancreatic cancer. I will also discuss nanobody-based CAR T cells.

Previous attempts to therapeutically target MUC1 failed because they targeted the tandem repeat domain, which is shed from tumor cells. Cancer cells express a cleavage product, MUC1*, that is the growth factor receptor that mediates tumor growth. We have two MUC1*-targeting CAR Ts in clinical trials where one bears the Tyr to Phe “1XX” mutations that slow signaling and greatly increase in vivo persistence. Both CAR Ts recognize the tumor via an antibody that binds to a cryptic site, that is only revealed when the transmembrane cleavage product MUC1* unfolds after cleavage and release of the tandem repeat domain.

• ​Solid tumors: What do we know? 
• Understanding the TME
• Targets for solid tumors
• Latest efforts to target solid tumors 

We utilize proprietary mRNADis and mSCAFold platform technologies to discover modules for cell engineering and processing. We will present preclinical studies of EPC-002, a human B7H3 armored CAR that simultaneously counters multiple mechanisms of TME immunosuppression and mediates persistent anti-tumor activity. EPC-002 is being advanced to clinic for resistant/refractory B7H3-positive solid tumor indications.

In solid tumors, CAR T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic/helper-dependent adenovirus (CAdVEC) that produces local oncolysis and expresses immunostimulatory molecules enhances the anti-tumor activity of adoptively transferred CAR T cells. Our preclinical results indicate that local treatment of CAdVEC can systemically enhance CAR T cell responses. We are now investigating this combination strategy in patients (NCT03740256).

Chimeric Antigen Receptor (CAR) T cell therapy has proven to be a powerful immunotherapy for hematologic malignancies. However, this success has not yet been transferred to solid tumors due to the immunosuppressive tumor microenvironment (TME). To provide a more favorable TME, we engineered CAR T cells targeting carbonic anhydrase IX (CAIX) secreting immune checkpoint inhibitors (ICIs) to rewire TME into active antitumor immunity for renal cell carcinoma (RCC) treatment.

The competition for scarce nutrients in the TME between tumor cells and T cells presents a major challenge to sustained T cell proliferation and function. To overcome these challenges, we have created a novel platform that enhances CAR T cell mobility and provides alternative fuel for T cell growth and function in the absence of glucose. This holds promise as a potential approach to enhance the effectiveness of CAR T cell therapy for solid tumor treatment.

This presentation will focus on: outlining a proteogenomic/immunopeptidomic platform for the identification of tumour-specific HLA-associated peptides from patient tumours; immunization and screening strategies to generate HLA/peptide-binding TCR-mimetic antibodies with high affinities and specificities; and optimizing TCR-mimetic antibody-based CAR design for maximal anti-tumour potency and benchmarking to TCR-based cell therapies.

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 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.

The clinical grade CellPryme technology is used to make better immune cells. CellPrymeM is a single 24-hour administration during the expansion stage of CAR-immune cell manufacturing that shifts cells towards a memory phenotype, conferring stronger persistence, less exhaustion, improved tumor trafficking/penetrance, and significantly improves tumor/cell killing. CellPryme-A is administered before and/or alongside a cell therapy to address the immunosuppressive tumour microenvironment.

First-generation CAR T cell therapies represent life-changing medical innovation and signal significant disruption in both healthcare delivery and reimbursement models, but they come with serious manufacturing, supply chain, and cost challenges. This talk will highlight some of the technology push, market pull, and regulatory innovations already underway which suggests next-generation cell-based immunotherapies will begin to address some of these challenges.

We have developed a novel, synthetic, circular coding RNA platform (oRNA technology) which exhibits significant improvements in production, expression, and formulation compared to mRNAs. Given the successes as well as remaining challenges with CAR T cell therapies, we combined our oRNA technology with novel immunotropic LNPs to create an off-the-shelf “autologous" in situ CAR (isCAR) therapy that effectively delivers anti-CD19 CAR to immune cells and regresses tumors in vivo.

Ex vivo CAR T cell therapies have proven successful in the clinic but still face significant challenges due to the elaborate and expensive engineering and manufacturing of T cells. Tidal Therapeutics has developed a new technology that allows the generation of CAR T cells directly in vivo. The technology uses mRNA, formulated in lipid nanoparticles that are specifically targeted to circulating T cells to transiently express CARs on the surface.