2G CARs containing a CD28 or 41BB endodomain elicit remarkable efficacy in hematological malignancies. 3G CARs contain both co-stimulatory units, although impact has been muted. We postulated that effective dual co-stimulation requires juxta-membrane positioning of these domains within separate receptors. We demonstrate that such parallel CAR T-cells resist exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling and metabolic fitness.

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.

One route to improve CAR T cell activity and safety is to engineer T cells for co-expression of the CAR and accessory molecules that address these clinical challenges. Most co-expression systems rely on the use of constitutive promoters for stable transgene expression, multiple viral vectors, or both, which adds cost and complexity to cell manufacturing, yields a non-homologous T cell product, and unregulated, constitutive expression of the accessory molecule. To improve CAR T cell manufacturing, activity and safety, we developed a single lentiviral vector system called UniVect that combines cell autonomous, antigen-induced production of a selected accessory molecule with constitutive expression of a CAR.

Dr. Ruella will discuss the recent developments in CAR T cell immunotherapy from his laboratory. He will discuss findings on the mechanisms of resistance to CART therapy and novel strategies to enhance CART functions. Finally, he will present recent data on the development of CART products for other hematological malignancies that do not express CD19.

A key question regarding cell therapies and antibodies is the existence of targets recognized by gamma delta T cells. We will present an extensive study of gamma delta T cells and ligands in solid tumors and leukemias.

While affinity of scFv is a poor predictor of CAR T-cell efficacy, overall binding strength (avidity) represents a crucial parameter for identifying and developing potent immunotherapies. Avidity reflects the bona fide interactions between T-cells and tumor cells and could therefore better predict effectiveness. The z-Movi^® Cell Avidity Analyzer is a unique instrument for direct measurement of cellular avidity providing a novel method to accelerate cell immunotherapy.

CAR-engineered T cell immunotherapy is under active investigation for the treatment of patients with advanced solid tumors, in light of the exceptional clinical responses seen in hematological malignancies, particularly CD19-targeting CAR T cells. However, major inhibitory mechanisms are hindering durable anti-tumor responses in solid tumors, which are addressing using novel combination therapies as well as innovative intrinsic editing approaches to improve overall anti-tumor immunity and durable therapeutic responses.

Neuroblastoma remains an incurable malignancy. GD2 is highly expressed on neuroblastoma tissue. We have developed an allogeneic T cell therapy approach utilizing genetic engineering of donor-derived T cells to express an anti-GD2DAR. Preclinical data demonstrate DAR-T has superior anti-tumor activity both in vitro and in vivo against neuroblastoma compared to CAR T cells. 

TIL therapy is a promising cell therapy approach. Both academic institutions and biotech companies have shown activity of TIL therapy in multiple cancer types, including melanoma, NSCLC, HPV-associated cancers, and others. TIL consists of deploying cancer-reactive tumor-infiltrated T cells, following in vitro re-activation and expansion, for therapy. Currently, of all cell therapies, TIL has been most successful. A randomized phase 3 trial in melanoma has almost finished accrual.

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.

Catalent will discuss a breadth of analytical methodologies facilitating manufacturing design and accelerating CAR-T therapies to commercial readiness phase.

Attendees will be able to gain insight into:

• Benefits of working with a full-service provider of analytical methods
• Strategy and process flow from analytical assay development to GMP implementation for clinical and commercial manufacturing