Glioblastoma cells showing glial cell marker GFAP in green and neuronal marker Tuj1 in red.
At the Abramson Cancer Center, Stephen Bagley, MD, MSCE, is collaborating with the principal investigators of the Amankulor and Binder/O'Rourke Labs to enroll patients in a pair of clinical trials focusing upon innovative immunotherapies—including CAR T-cell therapy—for patients with recurrent IDH-mutant glioma and glioblastoma.
Both trials were developed at Penn Medicine and the Abramson Cancer Center, origin of CAR T-cell therapy, the first cancer gene therapy approved for the treatment of leukemia and lymphoma, and of the first successful application of tocilizumab for cytokine release syndrome, a side effect of CAR T-cell therapy. These innovations set the stage in the years following for more than two dozen FDA approvals for new therapies in cancer and immunotherapy—including mRNA vaccines—at the Abramson Cancer Center, now one of the world's leading sources of research in immunotherapy and cancer genetics.
The current trials in IDH-mutant glioma and glioblastoma are open to patients whose cancers have recurred despite prior standard of care therapy, including radiotherapy and chemotherapy.
Using CAR T Cells to Target Receptors
CAR T-EGFR-IL13Ra2 in EGFR Amplified Recurrent GBM | NCT05168423
This Phase I trial is evaluating the safety, side effects, and best dose of autologous chimeric antigen receptor T cell (CAR T) EGFR-IL13Ra2 cells for the treatment of IDH wild-type epidermal growth factor receptor (EGFR) amplified glioblastoma multiforme (GBM) that has recurred in patients following prior first-line radiotherapy.
CAR T-EGFR-IL13Ra2 cells are designed to identify and target two different antigens, EGFR and IL13Ra2, that are commonly present on tumor cells and may offer a safe and effective way to control recurrent glioblastoma.
About Glioblastoma multiforme (GBM)
Glioblastoma multiforme (GBM) accounts for almost half of primary malignant brain tumors in adults. Except for certain heritable syndromes, the cause of GBM is unknown in most patients. GBM is an aggressive and highly infiltrative tumor that remains incurable in the vast majority of cases. Recurrence within two years of diagnosis occurs in ~90% of patients despite intensive oncologic therapy, including surgery, radiation, and chemotherapy.
About CAR T-EGFR-IL13Ra2 in GBM
CAR T cells possess many promising attributes for the treatment of recurrent GBM, not the least of which is the cells' capacity to migrate across the blood-brain barrier to target and kill malignant cells. Recent efforts to enhance the efficacy of CAR T have focused upon developing T cells that simultaneously target IL-13Rα2 and amplified/mutated EGFR, tumor-associated antigens that together promote GBM cell proliferation.
EGFR protein overexpression occurs in ~60% of glioblastoma phenotypes, and is characterized by maintenance and proliferation of cancer cells. Interleukin-13 Receptor Alpha 2 (IL13Ra2) is a high-affinity IL13 signaling receptor expressed in >80% of glioblastoma, but found nowhere else in normal tissue outside of the adult testes. In studies, IL-13 signaling through the IL13Ra2 receptor has been shown to mediate tumor migration and invasion.
Trial Objectives
The primary objective of this trial is to evaluate the safety of CAR T-EGFR-IL13Ra2 cells. Secondary objectives include study and manufacturing feasibility, and a description of preliminary efficacy. Exploratory objectives include a characterization of the pharmacokinetic profile and bioactivity of the CAR T-EGFR-IL13Ra2 cell; measuring CAR T-EGFR-IL13Ra2 trafficking to tumor; a determination of the incidence of CAR T-EGFR-IL13Ra2 escape, and an evaluation of correlative measures of CAR T-EGFR-IL13Ra2 cell activity and disease response.
Early findings from the CART-EGFR-IL13Ra2 in EGFR Amplified Recurrent GBM Clinical trial suggest that that this dual-target approach is an encouraging step toward developing effective, long-lasting therapies for solid tumors like GBM. Read more on Penn News.
Evaluating Tretinoin and Retifanlimab
Tretinoin and Retifanlimab in Patients with Recurrent IDH-Mutant Glioma | NCT05345002
A Phase II trial to evaluate the effectiveness of the combination of all-trans retinoic acid (ATRA, tretinoin) and retifanlimab for patients with recurrent IDH-mutant gliomas (astrocytoma or oligodendroglioma, any grade) who have progressed on prior therapy.
Immunotherapy with monoclonal antibodies, such as retifanlimab, may help the body's immune system attack cancers, and may interfere with the ability of tumor cells to grow and spread. Administering retifanlimab in combination with the synthetic retinoid tretinoin (ATRA) may be more effective at treating patients with recurrent IDH-mutant gliomas than giving either treatment alone.
About IDH-Mutant Glioma
Isocitrate dehydrogenase (IDH) mutant gliomas are a family of diffusely infiltrating primary brain tumors with a molecular profile distinct from that of glioblastomas, which are now defined as IDH-wildtype (IDHwt) tumors. The most common adult malignant primary brain tumor in patients younger than 50, IDH mutant gliomas range from low-grade to high-grade. While seizures are the predominant initial symptom in patients with low-grade IDH mutant gliomas, high-grade IDH mutant gliomas typically manifest as aggressive tumors with a faster clinical deterioration. The current standard of care for IDH mutant glioma includes maximal resection, when possible, followed by combination radiation and chemotherapy. However, these treatments offer limited survival benefit and may result in long-term toxicities, including cognitive decline. Moreover, there remains a significant unmet need for effective treatments for tumors that have recurred after prior radiation and chemotherapy.
About Tretinoin and Retifanlimab in IDH-Mutant Glioma
All-trans retinoic acid (ATRA) is made in the body from vitamin A and acts in its normal roles to modulate cellular proliferation and differentiation. In IDH-mutant cancers, the genes associated with retinoic acid metabolism are hypermethylated, resulting in an "ATRA-deficient" state. Preclinical data has suggested that restoration of ATRA stores by exogenous administration (i.e., oral administration of Tretinoin) may have anti-tumor effects that are immune-mediated.
Retifanlimab is a monoclonal antibody that targets cells expressing the checkpoint protein PD-1, including T cells, with the object of restoring their function in the immune system. PD-1 (programmed cell death 1) is a negative immunoregulatory human cell surface receptor. When bound to the protein PD-L1, PD-1 prevents T cells from killing other cells.
Trial Objectives
The primary objectives of this trial include the efficacy of tretinoin (ATRA) with retifanlimab as measured by overall response rate (percentage of patients who have achieved complete response, partial response, or minor response) in:
- Patients with recurrent IDH1/2-mutant gliomas who have progressed on temozolomide and another alkylator, and
- Among patients with recurrent IDH1/2-mutant gliomas that have failed one alkylator with equal to or more than 12 months since last treatment.
The trial also has a surgical arm that will enroll patients with a clinical indication for surgical resection of their tumors and will administer ATRA neoadjuvantly. Secondary objectives include the safety and tolerability of the combination of ATRA and retifanlimab in patients with recurrent IDH1/2 mutant glioma, and progression-free survival (PFS) and overall survival (OS) after treatment with the combination.
Clinical Trial Enrollment
To enroll a patient in either clinical trial, contact Molly Cassidy, MSN, RN, OCN, at 267-441-3463 or at Molly.Cassidy@pennmedicine.upenn.edu.