Solid tumor responses to CAR T cell therapy have been disappointing to date. To address this issue, we developed a new second generation CAR comprising a truncated human CD34, a scFV directed to Lewis Y, and endodomains CD28-CD3zeta in T cells that were enriched for 'early' T cells (stem cell and central memory-like). These "early" CAR T had enhanced proliferation, generating diverse progeny with increased cytotoxic function increased cytokine/chemokine secretion, and better in vivo therapy responses.

The overall binding strength (avidity) between cells is a crucial parameter for developing new immune cell therapies. An important obstacle is the lack of a fast and accurate technology to assess cellular binding avidity. The z-Movi^® is a novel and unique instrument for direct measurement of cell–cell binding avidity using acoustic forces. We demonstrate that binding avidity of CAR and TCR transgenic T cells to tumor cells strongly correlates with in vitro functionality.

We generated novel bispecific proteins to mediate the interaction between APCs and CAR T cells. We termed these bispecifics “Bispecific Engagers of APCs and T cells (BEATs)”. CAR T cell proliferation and function was significantly enhanced by BEATs in the presence of APCs in vitro and in vivo. Importantly, murine syngeneic and human xenograft solid tumor growth was significantly inhibited when CAR T cells were administered in combination with BEATs.

Gene editing experts within MilliporeSigma’s Cell Design Studio™ provide custom cell line engineering services to create and deliver unique cell-based assays tailored for drug discovery and preclinical manufacturing. Our cellular models have been used for applications such evaluating efficacy of CAR-T cells, screening candidate checkpoint inhibitors, and generating potency assays for therapeutic testing. In this presentation, we will discuss the technology of these lines, their utility in immuno-oncology and novel therapeutic testing.

Allogeneic CAR T cells have shown encouraging preliminary Phase I clinical data demonstrating the potential promise of this therapy for more patients. This talk will highlight the critical areas that need to be addressed to maximize the dissemination of allogeneic CAR T cells and our approach to engineer optimal CARs that specifically targets tumors across a range of hematological malignancies and solid tumors.

Gene editing can be used to generate off-the-shelf allogeneic CAR T cell products and to impart desirable features to improve their function. For our next generation of therapeutics, we are exploring gene knockout and incorporation of RNAi cassettes to modulate gene expression, with the goal of avoiding rejection, reducing T cell exhaustion, and enhancing function in the suppressive tumor microenvironment.

This presentation will discuss new bioluminescent tools to expedite the development of T cell-redirecting cancer therapies. First, we will describe two NanoBiT-based assay platforms that can quantitatively measure the potency of CD3 bispecific antibodies or BiTEs to induce T cell-dependent target cell killing and cytokine production. Next, we will describe TCRαβ-null reporter cell lines that can be used to screen transgenic TCRs against specific tumor antigen targets.

CAR T cells have proven successful in B cell malignancies but the unmet needs are still high in oncology. TALEN-mediated gene editing is highly efficacious, precise and specific. We are leveraging our expertise in gene editing to tailor properties of CAR T cells towards increasing their potency, rendering them resistant to tumor microenvironment while maintaining safety.

Targeting of CD3ζ by shRNA leads to efficient knockdown of the TCR complex, inhibiting GvHD in vivo and, importantly, allowing for increased persistence of T cells. Celyad’s “plug & play” shRNA allogeneic platform will be presented. Implementation of a T cell inhibitory peptide in the NKG2D CAR vector (CYAD-101) leads to blunting TCR activity and preventing GvHD. Clinical testing of CYAD-101 showed no significant toxicity and no GvHD. Clinical results will be presented.

This presentation will provide an overview of the mechanisms of resistance to CAR T immunotherapy and strategies to develop rationally designed, next-generation immunotherapies.

Redirecting the cytotoxicity of T cells by CD3-bispecific antibodies has resulted in remarkable clinical activity, albeit often accompanied by immune-related adverse events. IRAE is due to robust activation of T cells via CD3 rapid signaling, leading to severe cytokine storm that limits the dose of the drug, resulting in a narrow therapeutic index. To mitigate, a plethora of TCR-engaging strategies, such as modulating the affinity and epitope, are being explored.

Tumor infiltrating lymphocyte (TIL) therapy uses a patient’s own immune cells to attack cancer. Iovance is currently conducting pivotal studies in patients with metastatic melanoma and advanced cervical cancer. In addition, the company’s TIL therapies are being investigated for the treatment of patients with locally advanced, recurrent or metastatic cancers including head and neck and non-small cell lung cancer. Clinical studies of T cell therapy for blood cancers called peripheral blood lymphocyte (PBL) therapy are being planned.

In TIL therapy T cells are grown from solid tumor samples and expanded to large numbers ex vivo to be infused back to the patient. The therapy has been very successful in metastatic melanoma with a 42% clinical response rate at our institution and others with most of the responses being durable. Despite great results we are at this point investigating why the other half of the patients would not respond. Through molecular and immunological assays we are trying to define biomarkers that could predict response to therapy. Another focus of our research is to test the efficacy of TIL therapy in other solid tumor types.