Hope on the Horizon: New Developments in CAR T-Cell Therapy for Brain Cancer
Introduction
Immune cells are crucial in the fight against cancer and other diseases. T cells act as frontline soldiers, identifying targets and initiating a response. Although these cells can detect and attack cancer cells, tumors often evade or suppress their response, posing a significant challenge for our immune system.
Researchers are actively devising solutions to overcome this problem. One approach involves modifying cells to carry specialized receptors tailored to recognize specific targets. These receptors, referred to as chimeric antigen receptors (CARs) form the foundation of a treatment known as CAR T-cell therapy. While this treatment has revolutionized the management of leukemia and lymphoma, yielding complete remissions in certain cases, its efficacy in solid tumors like brain cancer has been limited. To bolster their effectiveness, scientists are exploring various strategies aimed at enhancing response rates and overcoming resistance. Recently, in two clinical trials, investigators implemented novel approaches in patients with a lethal form of brain cancer known as Glioblastoma.
Intrathecal CAR T cells Targeting EGFR and IL13Rα2 (UPenn)
A number of targets are commonly found on the surface of brain cancers, including EGFR, a growth receptor, and IL13Rα2, an immune modulator. In a phase 1 clinical trial conducted by investigators at the University of Pennsylvania, six patients with progressive, multifocal glioblastoma were enrolled. Immune cells were extracted from the patients and genetically engineered with receptors targeting both EGFR and IL13Rα2. The resulting CAR T-EGFR-IL13Rα2 cells were delivered intrathecally, with an injection into the cavity around the spinal cord, which helps them reach the brain. In all patients, there were measurable reductions in the size of tumors, suggesting that these cells were effective at mounting an immune response. These findings hold significance given the persistent challenge of recurrent glioblastoma, which often shows limited responsiveness to available treatments. While none of the patients achieved deep tumor shrinkage or complete remission, the trial suggests the potential of CAR T-cell therapy in glioblastoma. The administration of CAR T-EGFR-IL13Rα2 cells was not devoid of challenges, as it led to some serious adverse events, including neurotoxicity requiring symptomatic management with steroids and other medications.
Intraventricular CAR T cells Targeting EGFR and EGFRvIII (Dana-Farber)
Many glioblastomas heavily rely on EGFR as a receptor to fuel their growth. As tumors progress, they can exhibit EGFR overproduction or develop altered forms, such as an EGFRvIII variant, which intensifies its activity. EGFRvIII has drawn considerable attention in research studies. In a clinical trial at Dana Farber, three patients were treated with CAR T cells targeting EGFR and EGFRvIII. Immune cells were extracted from patients and modified with a receptor that targets EGFRvIII and releases a molecule called TEAM targeting normal EGFR overproduced by cancer cells. The resulting CARv3-TEAM-E T-cells were administered to patients through a catheter implanted in the brain (ventricular injection). Early scans revealed promising outcomes, with all three patients experiencing notable responses. For two the response was transient while one patient demonstrated a major reduction in tumor size for over 150 days. Only a few adverse effects were observed including fever, encephalopathy (characterized by symptomatic inflammation), and fatigue were observed in trial participants.
Conclusion
These groundbreaking trials underscore the potential efficacy of CAR-T cell therapy in glioblastoma treatment, offering valuable insights for future therapeutic approaches. The importance of targeting multiple receptors was evident in inducing responses, suggesting that future studies may explore additional targets to enhance treatment efficacy. However, sustaining these responses remains a challenge, requiring the exploration of novel CAR T-cell designs to improve durability. It is important to recognize that while CAR T-cell therapies hold promise for long-lasting responses, they also entail significant risks of serious adverse events. Furthermore, the manufacturing of these cells presents challenges, which explains the limited number of patients included in each study. For patients considering participation in T-cell therapy trials, open discussions with their healthcare providers are crucial. If no local trials are available, patients should inquire about referrals to centers offering this approach. However, it is essential to weigh both the potential benefits and risks of this treatment before making any decisions.