Immunotherapy and personalized medicines have taken center stage in cancer treatment over the last decade. Chimeric antigen receptor T- cell (CAR-T) therapy has gained much attention in this field by revolutionizing cancer treatment. Though these therapies have improved cancer survival rates, cancer is still the second most common cause of death in the United States. One of the significant drawbacks of CAR-T therapy is its limited success in treating solid cancer due to the complex microenvironment. Chimeric antigen receptor macrophages (CAR-M) have the potential to address that shortcoming.
What are Macrophages?
Macrophages are immune cells, which can regulate various physiological functions. Depending on the microenvironment, macrophages can either be pro-inflammatory (M1), leading to immune system activation, or anti-inflammatory (M2), leading to the production of growth factors and anti-inflammatory cytokines.
Macrophages are one of the first cells to enter the tumor microenvironment, as tumor cells take advantage of this particular property of the macrophages. The tumor microenvironment is conducive to an M2-like phenotype of macrophages, leading to the de-activation of the host’s immune response.
How Does CAR-M Work?
CAR-M therapy is very similar to CAR-T technology. Blood macrophages/monocytes are isolated from the patient, and the cells are then genetically altered to introduce foreign DNA to produce the chimeric antigen receptor on the macrophage surface.
Following the receptor’s expression, the macrophages are infused into the patient, where these chimeric receptor-containing cells can target cancer cells. These chimeric receptors identify the antigen on the cancer cells and phagocytose the cancer cells, thus destroying them. Once destroyed, the macrophage will act as an antigen-presenting cell (APC) to display fragments of the cancer cells which will, in turn, activate the T-cells.
The major hurdle in the CAR-M therapy technology is to alter the DNA of macrophages, as they are innately resistant to viral transduction.
In a preclinical proof of concept study, scientists from the University of Pennsylvania engineered the human epidermal growth factor receptor 2 (HER2) CAR-M cells. They demonstrated that a single cell infusion reduced the solid tumor load. Further, the CAR-M cells were able to activate the “M2”-anti-inflammatory macrophages in the tumor microenvironment to “M1”-pro-inflammatory states. The CAR-M cells further activated the innate immune system leading to T-cell proliferation.
This study was the basis of the first clinical trial with CAR-M cells. The lead author launched CARISMA therapeutics based on the findings of this paper.
CARISMA Therapeutics- The Pioneer in CAR-M therapy
CARISMA Therapeutics was launched in 2016 by Drs. Saar Gill and Michael Klichinsky and the company are the first to take CAR-M therapy to a Phase 1 clinical trial. The company’s drug candidate, CT-0508, is a HER2 targeting CAR-M therapy for patients with HER-2 overexpressing tumors.
If this drug candidate is successful in the clinics, CARISMA therapeutics plans to expand its portfolio of antigens and targets. The company has already released preclinical data of combination therapy of CAR-M and anti-PD1 therapy during the Annual Meeting of the Society of Immunotherapy of Cancer.
The First Clinical Trial
The Phase 1 clinical trial, which is aimed at testing the safety and efficacy of the CAR-M therapy, CT-0508, for treatment of HER2 positive cancer, has enrolled a total of 18 patients. The patients will receive an infusion of CAR-M cells, and the study will run from 2021 to 2023.
The first patient has already been injected with the CAR-M cells last month. This clinical study will not only test the safety of these types of therapies but will also be a trial for the cross-country manufacturing and delivery required for CAR-M. Dr. Debora Barton, the CMO of CARISMA Therapeutics, is cautious in her approach and said, “It’s a whole world of logistics that we need to get in place, and we have it in place, but you know there are snowstorms, and everything can happen. Everything can go wrong, and we’re taking all measures.”
The Stakeholders and Challenges
CARISMA Therapeutics raised $53 million as Series A funding in 2018. Abbvie and HealthCap have backed the startup company during the Series A funding. The company was able to raise another $6 million by extending the funding round.
Early last month, CARISMA Therapeutics announced that they had raised an additional $47 million as a part of the Series B funding. Symbiosis LLC, Livzon Pharmaceutical Group, among others, invested in this round. Abbvie further invested in this round as well, showing their faith in this new technology and therapy.
With no clinical data from the CAR-M therapy available, none of the big pharmaceutical companies other than Abbvie has taken a gamble to invest. It will be interesting to see if this early investment pays off for Abbvie, who has slowly started investing in CAR technology. It is to be noted here the CAR-M is not the only technology that has the potential for solid cancer treatment. Biopharmaceutical companies are also investing in producing CAR-natural killer (NK) cells which have the potential to treat cancer with these cells already in clinical trials.
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