Results of preclinical studies showed that an approach involving injection of antigen linked to an amphiphilic molecule (ie, an amphiphilic “vaccine”) subsequent to delivery of CAR-T cells expressing an engineered receptor specific for that antigen results in the activation, proliferation, differentiation, and enhanced survival of CAR-T cells, as well as stimulation of endogenous immunity, in the setting of solid tumors. The findings from this study were published in Science.1

Two CAR-T cell therapies involving T cells engineered to express the B-cell antigen, CD19, have been approved by the US Food and Drug Administration (FDA) for the treatment of some patients with certain hematologic malignancies (eg, large B-cell lymphoma, acute lymphoblastic leukemia).

Nevertheless, numerous challenges must be overcome if this type of approach is to be successfully applied in patients with solid tumors.

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To be effective, engineered CAR-T cells must travel to and infiltrate the tumor microenvironment — as well as survive in that environment. However, several previous studies in solid tumors have showed that CAR-T cells rapidly become dysfunctional at the tumor site, possibly due to a tumor-generated immunosuppressive environment.

In this study, researchers from the Massachusetts Institute of Technology, Cambridge, hypothesized that using a vaccine-based approach to stimulate CAR-T cells could potentially overcome tumor-related immunosuppression of CAR-T cells in solid tumors.

Previous work by this group showed that amphiphilic, antigen-linked “vaccines” bind albumin in the blood and are primarily delivered to lymph nodes, which are densely populated with immune cells.

In this study, a fluorescent dye (fluorescein isothiocyanate, or FITC) that was attached to an amphiphilic phospholipid polymer was shown to primarily partition into the cell membranes of antigen-presenting cells in the lymph nodes, with the attached antigen displayed on the surfaces of these cells. In order to eliminate the need for a ligand-specific vaccine, the study authors developed a bispecific CAR targeted to both tumor antigen and FITC.

These antigen-presenting cells were shown to stimulate CAR-T cells characterized by a FITC-binding receptor in a dose-dependent manner, leading to the death of the antigen-presenting cells.

Furthermore, results of in vivo experiments performed in mice that involved injection of an FITC amphiphilic vaccine and adjuvant twice versus no vaccine injection following delivery of CAR-T cells engineered to express an FITC-specific receptor showed enhanced T-cell proliferation with the former approach.

Specifically, the vaccine-based approach yielded “a CAR-T population nearly double the size achieved by administering a 200-fold–greater number of CAR-Ts without vaccination,” the study authors noted.

In addition, in vivo experiments performed in mice with EGFRvIII-positive tumors, showed improved cell proliferation and survival of CAR-T cells engineered to recognize EGFRvIII, as well as infiltration into the tumor, with subsequent delivery of EGFRvIII-amphiphilic vaccine compared with an approach not involving administration of the vaccine. 

Notably, EGFR-specific CAR-T cells administered without the vaccine had no effect on tumors, whereas infusion of CAR-T cells followed by administration of EGFRvIII amphiphilic vaccine eliminated tumors in a majority of the mice.

Interestingly, EGFRvIII CAR-T cells from vaccinated mice were shown to persist over time, and these mice rejected EGFRvIII-positive tumor cells administered over 2 months following the initial treatment. Furthermore, these mice also rejected tumor cells lacking the EGFRvIII antigen that were subsequently injected into the animals.

While results of in vitro experiments showed the bispecific CAR-T cells were as effective as the CAR-T cells targeted to tumor antigen alone with respect to killing tumor target cells, vaccination of mice with FITC-amphiphilic vaccine “led to pronounced CAR-T expansion in the periphery and increased tumor infiltration with minimal serum cytokine elevation and transient fluctuations in body weight after each vaccination.”1

“The conceptual innovation of the approach taken by Ma et al. is to bypass the major histocompatibility complexes that present antigens to T-cell receptors needed for traditional vaccine responses, while preserving the immune stimulation provided by vaccination,” noted Nathan Singh, MD, Washington University School of Medicine, St. Louis, Missouri, and Carl H. June, MD, Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, who were the authors of an accompanying editorial.2

Drs Singh and June further commented that “another conceptual innovation of this approach is that it uses the CAR not only for tumor targeting but also as a machine to enhance T-cell activity, demonstrating that this chimeric molecule may have multifunctionality.”2

Finally, the study authors noted that this vaccine-based approach “can be applied to existing CAR-T designs.”1

References

  1. Ma L, Dichwalkar T, Chang JYH, et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science. 2019;365:162-168.
  2. Singh N, June CH. Boosting engineered T cells. Science. 2019;365:119-120.