A chimeric antigen receptor therapy based upon macrophages (CAR-M) is currently being evaluated in a first-in-human Phase 1 multi-center clinical trial at the Abramson Cancer Center and four other locations.
CAR-macrophages for the Treatment of HER2 Overexpressing Solid Tumors
The study is focusing upon patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-targeted therapies, or who do not respond to treatment.
The therapy, and consequent clinical trial, were developed by Saar I. Gill, MD, PhD, hematologist at the Abramson Cancer Center, and partners in private industry.
What are CAR Macrophages?
Macrophages are unique antigen-presenting cells that participate in both the innate and adaptive immune response to physiologic insult.
M1-type macrophages emit pro-inflammatory cytokines, present antigens to T cells, and participate in the positive immune response. M2-type initiate and direct T cells/adaptive immunity, secrete anti-inflammatory cytokines to reduce inflammation, buffer the immune response, and promote wound healing and tissue repair.
In providing these polar opposite responses, macrophages work in concert within the immune system to first eliminate foreign microbes and other invaders, and to promote healing thereafter.
However, solid tumor cancers are an exception.
Solid Tumor Microenvironment
In the solid tumor microenvironment (TME), M1 macrophages are recruited by cytokines and chemokines, and mistakenly recognizing the tumor as tissue in need of repair, convert to M2 type cells to promote angiogenesis and suppress the native immune response. The resulting TME presents an inhospitable platform for immunotherapy, one that CAR T cell therapy has thus far been unable to transcend, largely as a result of the immunosuppression inculcated by macrophages.
Other barriers include the great level of antigen heterogeneity in tumor cells and the dearth of tumor-specific antigens, the latter substantially elevating the risk of off-tumor toxicity with CAR T therapy.
Macrophages as Targets of Immunotherapy
Despite their role in tumor progression and immunosuppression, macrophages present an appealing target for immunotherapy.
As noted, the M1 type are capable of phagocytosis, cytotoxicity, and antigen presentation to T cells; the M2 type have the capacity to pervade the tumor microenvironment. If, then, the M2 type could be converted back to an M1 type after infiltrating a tumor (a process known as repolarization), macrophages could play an important role in solid tumor immunotherapy.
The application of macrophages in solid tumor immunotherapy is not new — but previous attempts, while demonstrating safety and feasibility, have failed to show notable anti-tumor efficacy. These efforts were based, however, on the premise of adoptive transfer of high numbers of autologous macrophages into the tumor environment.
Dr. Gill and colleagues hypothesized that the expression of CARs in human macrophages could redirect their phagocytic function and result in a targeted anti-tumor therapeutic effect with the potential to stimulate an adaptive immune response. The team subsequently developed a CAR based upon a canonical signaling molecule for antibody-dependent cellular phagocytosis in macrophages, and evaluated it for efficacy in several murine models.
In the first of these investigations, the engineered CAR-Ms were found to elicit phagocytosis of solid tumor antigen-bearing mesothelin and HER2 cells in an antigen-specific manner.
With supporting evidence for anti-tumor phagocytic activity, efforts to translate the platform to primary human macrophages were initiated by examining the long-standing challenge of gene transfer into primary human macrophages. Using a docking protein for group B adenoviruses and a replication-incompetent chimeric adenoviral vector as a method of CAR delivery, the team produced human macrophages that expressed CAR with high efficiency and reproducibility between donors.
Further characterization of CAR-M activity, according to a report in Nature Biotechnology authored by Drs. Gill and Carl H. June, among others at the Perelman School of Medicine, demonstrated that CAR-Ms "expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity."
CT-0508: FDA Fast-Track Designation
Now known as CT-0508, Dr. Gill's CAR-Ms received fast-track designation from the Food and Drug Administration for the treatment of patients with solid tumors, last fall.
The first-in-human trial underway at the Abramson Cancer Center is being led by principal investigator Kim Reiss-Binder, MD.
Dr. Reiss-Binder noted in a recent interview that the potential of CAR-M cell therapy to address HER2-positive solid tumors was a reflection of the cell's capacity to engage tumors differently by penetrating them to induce a reaction. A characteristic, she said, that "makes CAR macrophage therapy quite different than CAR T cells, and something we are enthusiastic about studying further."
Scientific Co-Director, Cell Therapy and Transplant Program, Dr. Gill shares Dr. Reiss-Binder's enthusiasm for CAR M therapy and the evolving trial.
"Seeing macrophages show high CAR expression, viability, and purity, successfully manufactured from cancer patients and well tolerated, has us excited to be conducting this trial to help us understand the impact CAR-M cells have on targeting solid tumors."