A Rundown of New Developments in CAR T-cell Therapy

INTRODUCTION

In February of 2022, Carl June and David Porter of the University of Pennsylvania reported in Nature that two of the people treated with Chimeric Antigen Receptor T (CAR T)-cell cancer therapy are still in remission 12 years after treatment. June went so far as to assert that CAR T-cell therapy can actually cure some patients with leukemia.^{1 2}

The National Cancer Institute describes CAR T-cell therapy as a type of treatment in which a patient’s T cells are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. CAR T-cell therapy is used to treat certain blood cancers.³

In the past 12 years, CAR T cells undoubtedly have been the basis of some remarkable cancer treatment advances, but with some definite limitations including the complexity and cost of manufacturing treatments and the difficulty of penetrating the solid tumor microenvironment. Additionally, CAR T-cell therapies may cause serious side effects including cytokine release syndrome, which may even be life-threatening. One CAR T-cell therapy trial was paused recently after two patient deaths were reported.⁴ Researchers and biopharma companies continue to search for and test new developments to address these limitations.⁵

ADVANCES IN PRODUCTION AND DELIVERY

One of the biggest limitations in CAR T-cell therapy is the cost and time required for manufacturing the treatment, and the limited number of institutions that can provide the treatment. The process involves many complex steps including extracting the patient’s T cells, engineering the CAR that directs the T cell to the cancer, growing the CAR T-cells in the lab, and re-infusing them into the patient. This process is extremely expensive and, according to the NCI, can take from 2 to 8 weeks. Many new approaches are being investigated to improve the manufacturing and delivery process.

• Off the shelf (allogeneic) versus individualized (autologous) CAR T-cell therapy. One possible method of making CAR T-cell therapy accessible to more people is to move from developing the treatment from a patient’s own cells to developing it from T cells of a healthy donor. Manufacturing T cells for possibly dozens of people at a time might reduce overall costs and allow hospitals to keep the cells on ice, making it possible to treat people at more facilities.⁶Another approach being developed by several biotechnology companies is using induced Pluripotent Stem Cells (iPSC) as precursors to T cells that can be edited to add the CAR and made to form T cells in cell banks.⁷
• Shortened manufacturing time. Even as new approaches are being studied, researchers at Penn Medicine (who helped pioneer CAR T-cell therapy) recently published an article about improvements to the existing autologous manufacturing process. They reported on a pre-clinical study showing that functional CAR T cells can be grown within 24 hours from T cells harvested from peripheral blood without the need for T cell activation or ex-vivo expansion. The efficiency of the process appears to be influenced by the formulation of the medium and the surface-area-to-volume ratio of the vessel.⁸
• New in vivo approaches. Several innovative methods are in pre-clinical development to find an in vivo approach to developing CAR T cells. For example, researchers at NC State and UNC Chapel Hill have developed an implantable scaffold that manufactures and releases CAR T cells in the body. The Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER) is seeded with human blood cells and CD19-encoding retroviral particles to deliver the appropriate interface for viral vector-mediated gene transfer, and implantation, mediates the release of functional CAR T cells in mice.⁹

Other in vivo approaches include gene therapy via fusogen delivery vehicles that bind to targeted T cell surface proteins and platforms that use small-molecule bispecific adapters to tag tumors.¹⁰

ADVANCES IN TARGETING SOLID TUMORS

Another limitation of CAR-T based cancer treatments is their apparent lack of efficacy with solid tumors. According to the National Cancer Institute web site, six CAR T-cell therapies have been approved by the FDA for blood cancers, and while CAR T-cell therapy has been studied for solid tumors such as breast and brain cancer, its use remains experimental. There are a number of new approaches being studied to improve the efficacy of CAR T-cell therapy in solid tumors.

• Combination with mRNA vaccine. One new approach being developed by BioNTech is a combination of CAR T-cell therapy with an mRNA vaccine encoding for the same protein being targeted by the cell therapy. This approach is designed to assist the CAR T cells in expanding and persisting in the body, which might make them more successful at treating solid tumors. Early results from small Phase I study were announced at AACR2022 and were encouraging in both safety and efficacy in tumor killing.¹¹
• Combination with oncolytic virus. Another innovative tactic devised by Mayo Clinic researchers combines CAR T-cell therapy with a cancer-killing virus. This dual therapy of a virus-loaded CAR T cell was demonstrated to target and treat solid cancer tumors more effectively than either the CAR T-cell therapy or the virus alone in a pre-clinical model.¹²
• “Armored” CARs. T cell exhaustion and hostile signals in the tumor microenvironment make it difficult for CAR T cells to treat solid tumors. Researchers are developing an “armored” CAR T cell that may address these issues. For example, one researcher is investigating a CAR cell that is resistant to TGF-beta, a protein that can help shut down T cells and help cancer cells avoid detection from the immune system.¹³
• Reconditioning the tumor microenvironment. Penetrating the solid tumor microenvironment including the stroma and the vasculature is challenging for CAR T cells. Researchers have identified PAK4, a protein kinase that regulates aberrant vascularization. A preclinical study showed PAK4 reduces vascular abnormalities, improves T cell infiltration, and inhibits glioblastoma growth in mice.¹⁴

SUMMARY

In summary, CAR T-cell therapy for blood cancers may provide long-term remission for some patients, but their clinical benefit is limited by the complexity and cost of manufacturing and lack of efficacy in solid tumors. New developments in the field, however, offer hope to patients of greater availability and efficacy in more types of cancer.