Clinical Development of CAR T Cell Therapy Targeting CD70 in Primary Glioblastoma
Abstract
Background: The brain is the most frequent site of crippling and incurable human disease, and brain tumors alone account for more than 100,000 deaths each year in the United States. The most common malignant primary tumor, glioblastoma (GBM), the same tumor that affected Senators Edward Kennedy and John McCain, will arise in more than 15,000 other Americans this year and is uniformly lethal. In adults, malignant primary brain tumors alone are more common than Hodgkin’s disease and cause more deaths than melanoma or cancers of the bladder or kidney. In children, brain tumors are the second most frequent malignancy (have surpassed leukemia to become #1 cancer in children of a certain age), and the most common cause of solid tumors. Furthermore, brain tumors are now the leading cause of cancer-related deaths in children under the age of 20 in the United States. However, treating patients with GBM is a special challenge because of the irreversible effects that standard treatments have on neurocognitive functions and quality of life; and mostly, the GBMs remain virtually incurable. Cancer (GBM) immunotherapy (The FY19 PRCRP Topic Areas) has represented one of the most promising new treatment strategies for cancer patients. Modification using genetic engineering of a patient’s own immune cells (called T cells), is a uniquely specific and promising approach for redirecting ordinary T cells into tumor-killer T cells. The treatment using this approach is called chimeric antigen receptor (CAR) T therapy. This technology has produced remarkable responses in both children and adults with refractory cancers and resulted in new Food and Drug Administration indications for the treatment of hematologic malignancies. However, CAR T cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Up to now, very few tumor-specific targets have been discovered in GBM. Thus, identifying useful clinical targets and developing effective therapeutic approaches are desperately needed. Currently, only three targets (EGFRvIII, Her2, and IL- 13Ra2) have been testing in clinical trials. Our Research: Our team recently identified a novel drug target, called CD70. To our knowledge, we are the first team to carry out comprehensive studies of the clinical relevance of CD70 expression in human gliomas. We found that CD70 expression on the tumor is an indicator of poor-survival for patients with gliomas, which makes this molecule to be an attractive tumor target for the CAR T cells therapeutics. Our team has published studies that show that CD70 CAR T cells are able to kill CD70 expressing GBM. In this proposal, we tackled the key obstacle of the CAR T cell therapy in solid tumors by modifying the CD70 CAR with IL-8 receptor. Our results show that the modified CD70CAR T cells induce a potent antitumor efficacy (100% mice were cured) in GBM models. Intriguingly, these T cells can also cure late-stage tumors, which is potentially a life-saving solution for the patients that surgical removal is not an option. Research Design: (1) We will determine the mechanisms by which CD70 expression leads to glioma-induced immunosuppression in a collaborative effort with Dr. Betty Kim, at MD Anderson Cancer Center. (2) Our published and preliminary data support a compelling rationale for the clinical evaluation of chemokine receptor-modified CD70 CAR T cell therapy in patients with GBM. We have finished the toxicology of the modified CD70 CAR T study in animals and found no CAR T therapy-related toxicity. With a completion and submission of IND (IMPACT: IL-8R Modified Patient-derived Activated CD70 CAR T cell Therapy) expected in November 2019, a conservative dose-escalation trial using a classic 3 + 3 design to evaluate primary clinical endpoints of feasibility and safety of intravenously delivered CD70 CAR T cells will be evaluated. We have go
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010726
Entities
People
- Jianping Huang
Organizations
- United States Army
- University of Florida