The present invention relates to immune cell-based anti-cancer therapeutics and methods of using the therapeutics in the treatment of cancer.

Universal chimeric antigen receptor expressing immune cells for targeting of diverse multiple antigens and method of manufacturing the same and use of the same for treatment of cancer, infections and autoimmune disorders

Chimeric antigen receptor T cell (CAR-T) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin's lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we employed single cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and post-infusion into NHL patients. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a non-proliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate TIGIT blockade alone improves the anti-tumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in NHL patients.

Sequential single cell transcriptional and protein marker profiling reveals TIGIT as a marker of CD19 CAR-T cell dysfunction in patients with non-Hodgkin's lymphoma.

Chimeric antigen receptor (CAR) T cells, which express a synthetic receptor engineered to target specific antigens, have demonstrated remarkable potential to treat haematological malignancies. However, their transition beyond haematological malignancy has so far been unsatisfactory. Here, we discuss recent challenges and improvements for CAR T cell therapy against solid tumors: Antigen heterogeneity which provides an effective escape mechanism against conventional mono-antigen-specific CAR T cells; and the immunosuppressive tumor microenvironment which provides physical and molecular barriers that respectively prevent T cell infiltration and drive T cell dysfunction and hypoproliferation. Further, we discuss the application of CAR T cells in infectious disease and autoimmunity.

CAR T Cell Immunotherapy Beyond Haematological Malignancy

The tumor microenvironment restricts the function and survival of various immune cells by up-regulating inhibitory immune checkpoints, and participates in the immune escape of tumors. The development of immunotherapies targeting immune checkpoints, such as programmed cell death receptor 1 antibody and anti-cytotoxic T lymphocyte-associated antigen 4 antibody, has provided many options for cancer treatment. The efficacy of other immune checkpoint inhibitors is also under development and research. Among them, T cell immunoreceptor with Ig and ITIM domains (TIGIT) has shown excellent clinical application prospects. Correspondingly, poliovirus receptor (PVR, CD155), one of the main ligands of TIGIT, is mainly expressed in various human malignant tumors and myeloid cells. CD155 interacts with TIGIT on natural killer cells and T cells, mediating inhibitory immunomodulatory regulation. This study summarized the mechanism of CD155/TIGIT in regulating immune cells and its role in the occurrence and development of digestive system tumors, aiming to provide a new perspective for immunotherapy of digestive cancers.

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Role of CD155/TIGIT in Digestive Cancers: Promising Cancer Target for Immunotherapy

Introduction The development of therapeutic antibodies targeting immune checkpoint molecules (ICMs) that induce long-term remissions in cancer patients has revolutionized cancer immunotherapy. However, a major drawback is that relapse after an initial response may be attributed to innate and acquired resistance. Additionally, these treatments are not beneficial to all patients. Therefore, the discovery and targeting of novel ICMs and their combination with other immunotherapeutics are urgently needed.Areas covered There has been increasing evidence of the CD96-TIGIT axis as ICMs in cancer immunotherapy in the last five years. This review will highlight and discuss the current knowledge about the role of CD96 and TIGIT in hematological and solid tumor immunotherapy in the context of empirical studies and clinical trials, and provide a comprehensive list of ongoing cancer clinical trials on the blockade of these ICMs, as well as the rationale behind combinational therapies with anti-PD-1/PD-L1 agents, chemotherapy drugs, and radiotherapy. Moreover, we share our perspectives on anti-CD96/TIGIT-related combination therapies.Expert opinion CD96-TIGIT axis regulates anti-tumor immune responses. Thus, the receptors within this axis are the potential candidates for cancer immunotherapy. Combining the inhibition of CD96-TIGIT with anti-PD-1/PD-L1 mAbs and chemotherapy drugs has shown relatively effective results in the context of preclinical studies and tumor models. 

Advances in therapeutic targeting of immune checkpoints receptors within the CD96-TIGIT axis: clinical implications and future perspectives

PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells.

Disclosed herein are switches for regulating the activity of a chimeric antigen receptor effector cells (CAR-ECs). The switches generally comprise a chimeric antigen receptor-interacting domain (CAR-ID) and a target interacting domain (TID). The switch may further comprise a linker. Further disclosed herein are methods of using the switches for the treatment of one or more conditions or diseases in a subject in need thereof.

Optimized chimeric receptor t cell switches and uses thereof

CD19 targeting chimeric antigen receptor (CAR) T cells have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, recent clinical data indicate that a significant portion of patients still do not benefit from the therapy owing to various resistance mechanisms, including high expression of multiple inhibitory immune checkpoint receptors on activated CAR T cells. Here, we report a lentiviral two in one CAR T approach in which two checkpoint receptors are downregulated simultaneously by a dual short hairpin RNA (shRNA) cassette integrated into a CAR vector. Using this system, we evaluated CD19 targeting CAR T cells in the context of four different checkpoint combinations PD1/TIM3, PD1/LAG3, PD1/CTLA4 and PD1/TIGIT and found that CAR T with PD1/TIGIT downregulation uniquely exerted synergistic antitumor effects in mouse xenograft models compared with PD1 downregulation only, and maintained cytolytic and proliferative capacity upon repeated antigen exposure. Importantly, functional and phenotypic analyses of CAR T cells as well as analyses of transcriptomic profiles suggested that downregulation of PD1 enhances short term effector function, whereas downregulation of TIGIT is primarily responsible for maintaining a less-differentiated/exhausted state, providing a potential mechanism for the observed synergy. The PD1/TIGIT downregulated CAR T cells generated from diffuse large B cell lymphoma patient derived T cells using a clinically applicable manufacturing process also showed robust antitumor activity and significantly improved persistence in vivo compared with conventional CD19 targeting CAR T cells. Overall, our results demonstrate that the cell intrinsic PD1/TIGIT dual downregulation strategy may prove effective in overcoming immune checkpoint mediated resistance in CAR T therapy.

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Simultaneous, cell-intrinsic downregulation of PD-1 and TIGIT enhances the effector function of CD19-targeting CAR T cells and promotes an early-memory phenotype

Xinxin Wang

Papers

PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells.

Optimized chimeric receptor t cell switches and uses thereof

Simultaneous, cell-intrinsic downregulation of PD-1 and TIGIT enhances the effector function of CD19-targeting CAR T cells and promotes an early-memory phenotype