Beyond Blood Cancers: Evolution of Next Gen CAR-T cell therapies

CAR T-cell (Chimeric Antigen Receptor T-cell) therapy supercharges a patient's own immune system to fight cancer. By engineering patient's T-cells to precisely target and destroy cancer cells, this revolutionary approach overcomes the limitations of the body's natural defenses, offering new hope in the fight against blood cancers. In autologous CAR-T cell therapy, T cells are extracted from a patient's blood, engineered with cancer-targeting receptors, and reintroduced, creating a powerful, personalized, and potentially long-lasting defense against the disease.

This therapy, also touted as the “living drug” in recent years has achieved remarkable success in treating hematological cancers with a reduction of remission rates of up to 80% in acute lymphoblastic leukemia and B-cell disorders such as non-Hodgkins’ lymphoma.









Since the first CAR-T cell therapy Kymriah (tisagenlecleucel) was FDA approved in 2017 against CD19 for acute lymphoblastic leukemia (ALL), there have been several more CAR-T cell therapy products that have been approved for lymphomas, certain forms of leukemia, and more recently, multiple myeloma. All approved therapies target specific proteins (antigens) found on the surface of B cells, namely CD19 or BCMA (B cell maturation antigen). Dual targeting of CD19/CD22 and CD19/BCMA with CRISPR Cas9 based gene editing has shown promising clinical trial results in B-cell malignancies.



Although CAR T-cell therapy has been a phenomenal success, several limitations and challenges hinder the utilization of its full potential. Immunologic functions of CAR-T cells can be hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment resulting in eventual exhaustion of T-cells and frequent severe toxicities arising from the immune response itself. Unlike hematological malignancies, targeting solid tumors has been significantly challenging. Solid tumors are characterized by a dense and protective microenvironment, making it difficult for CAR-T cells to infiltrate and effectively eliminate cancer cells. Additionally, the heterogeneity of solid tumors, with varying antigens expressed on different cells, further complicates targeting. To address all these limitations, new generations of CAR-T cells with enhanced capabilities are being developed, to release localized doses of therapeutic cytokines, immunostimulatory ligands, or antibody fragments. The recent FDA approval of TECELRA (afamitresgene autoleucel) for adults with advanced synovial sarcoma represents a major breakthrough in autologous T cell immunotherapy and a significant step forward for CAR-T cell therapy in treating solid tumors.

Researchers from the Perelman School of Medicine at the University of Pennsylvania demonstrated the potential of "dual-target" CAR T cell therapy in combating glioblastoma (GBM), an aggressive brain cancer (by targeting two proteins EGFR and IL13Rα2 found in most GBMs)

This dual-pronged attack aims to overcome the tumor's diversity and increase the likelihood of eliminating a broader spectrum of cancer cells. For targeting antigen negative tumor cells that are hard to treat with traditional CAR-T cell therapies, scientists have developed a strategy to combine cell therapy and pro drugs. A novel class of CAR-T cells that are programmed to activate systemically administered inactive prodrugs at tumor sites, called SEAKER cells (Synthetic Enzyme-Armed KillER), generate enzymes that activate the small molecule prodrug catalytically, in situ at a tumor site.

While promising, its limitations, such as tumor relapse, drug resistance, toxicity, and the risk of severe side effects like Cytokine Release Syndrome (CRS), prevent it from being a first-line treatment. Increasing the dose of CAR-T cells can reduce relapse but exacerbates CRS risk.

Recent research has unveiled the potential of stem memory T cells (TSCM) to improve CAR-T therapy. TSCM cells, a unique type of memory T cell, offer enhanced safety and efficacy. They are less differentiated, allowing for self-renewal and differentiation into various T cell types. TSCM-based CAR-T cells have demonstrated reduced CRS and neurotoxicity, coupled with long-term persistence.

Furthermore, scientists are developing innovative next-generation T cell therapies that can be precisely controlled using small molecule drugs. These engineered "on-off switch" CAR T-cells may improve safety by reducing side effects and enhance effectiveness by allowing for periods of rest, potentially leading to longer-lasting cancer control.

Emerging Single-cell (sc) sequencing technologies are poised to revolutionize CAR-T cell therapy. Techniques like single-cell (sc) RNA-seq, scTCR-seq (T-cell Receptor sequencing), scATAC-seq (transposase-accessible chromatin sequencing), CyTOF (cytometry by time-of-flight), CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), and sc proteomics offer unprecedented resolution to explore cellular heterogeneity and molecular landscapes. Early studies have already demonstrated the potential of these technologies to identify optimal CAR T-cell targets and treatment strategies.

These breakthroughs hold significant promise for cancer immunotherapy, particularly in treating solid tumors and autoimmune diseases.