CAR T Cell Therapy's Potential for Pediatric Brain Tumors

Abstract

Malignant central nervous system tumors are the leading cause of cancer death in children. Progress in high-throughput molecular techniques has increased the molecular understanding of these tumors, but the outcomes are still poor. Even when efficacious, surgery, radiation, and chemotherapy cause neurologic and neurocognitive morbidity. Adoptive cell therapy with autologous CD19 chimeric antigen receptor T cells (CAR T) has demonstrated remarkable remission rates in patients with relapsed refractory B cell malignancies. Unfortunately, tumor heterogeneity, the identification of appropriate target antigens, and location in a growing brain behind the blood-brain barrier within a specific suppressive immune microenvironment restrict the efficacy of this strategy in pediatric neuro-oncology. In addition, the vulnerability of the brain to unrepairable tissue damage raises important safety concerns. Recent preclinical findings, however, have provided a strong rationale for clinical trials of this approach in patients. Here, we examine the most important challenges associated with the development of CAR T cell immunotherapy and further present the latest preclinical strategies intending to optimize genetically engineered T cells' efficiency and safety in the field of pediatric neuro-oncology.

Keywords: T cell; atypical teratoid rhabdoid tumors; chimeric antigen receptor; ependymoma; high-grade glioma; medulloblastoma; pediatric brain tumor; radiotherapy; tumor microenvironment.

Figure 1

Strategies for improving the efficacy of CAR T cell therapy in pediatric brain tumors. Top left: CAR T cell trafficking into the tumor site depends on the expression of receptors for chemokines secreted by the tumor. CAR T cells endogenously express chemokine receptors, but their respective ligands are not expressed by tumor cells. CAR T cells can be engineered to express receptors (e.g., CCR4) for chemokines secreted by tumor cells to improve CAR T cell homing to tumors. Alternatively, CAR T cell infusion can be combined with radiation therapy, which induces the release of proinflammatory cytokines to increase CAR T cell recruitment into the tumor. Bottom: Tumor cells escape CAR T cell killing by downregulating CAR target expression. CAR target expression can be induced using epigenetic molecules. Bi- or multispecific CAR T cells can be used to avoid the emergence of antigen-negative tumor clones. Antigen-activated CAR T cells in the TME upregulate immune checkpoint molecules that induce T cell dysfunction and tumor escape. ICM inhibitors can be used as adjunct therapy, or CAR T cells can be genetically modified to avoid the expression of ICM receptors and T cell dysfunction. Top right: The hypoxic tumor microenvironment is rich in soluble factors such as immunosuppressive cytokines and tumor metabolites that can inhibit CAR T cells directly or indirectly. A2AR genetic depletion in CAR T cells increases T cell resistance to adenosine. Glutaminolysis inhibitors, CAR design, and/or T cell engineering impact CAR T cell fitness and antitumor efficiency. CAR T cells can be further engineered to express activating receptors specific for immunosuppressing cytokines present in the TME. Lastly, adjunct radiotherapy can be used to tame the immunosuppressive TME and increase CAR T cell antitumor activity.

Figure 2

CAR T cell migration across the blood–brain barrier in pediatric brain tumors. Bottom: Tight junctions between endothelial cells limit the passage of CAR T cells. Interaction with P-selectin decreases T cell velocity in capillaries. Integrin α4β1 receptor engagement by VCAM1 proteins expressed by endothelial cells initiates T cell arrest followed by T cell diapedis. Middle: Pericytes and astrocyte endfeet further impede T cell trafficking into the brain parenchyma. Top: Tumor cells within the brain parenchyma may recruit T cells through chemokine production as indicated.