An experimental immunotherapy using chimeric antigen receptor macrophages (CAR-M) is safe and helps activate the body’s immune system against certain solid cancers, UNC Lineberger researchers and their colleagues report in Nature Medicine.
Preliminary findings from an early-stage clinical trial demonstrated that CT-0508 temporarily stopped the growth of tumors with high levels of human epidermal growth factor receptor 2 (HER2), a protein that regulates cell growth. While CAR-M therapy faced challenges such as limited persistence in tumors and sustaining immune activation, the study underscores its potential as a promising alternative to CAR-T therapy.
CAR-T and other adoptive cell therapies work well in some blood cancers but struggle in solid tumors due to factors like heterogeneous antigen expression, limited tumor infiltration, and an immunosuppressive microenvironment that hinder their effectiveness. In addition, suboptimal immune cell proliferation and function limit sustained tumor control, further undermining the impact of conventional adoptive cell therapies in solid tumors.
“Unlike traditional immune effector cells, macrophages are naturally abundant in solid tumors and can be genetically modified to enhance their antitumor activity. This study demonstrates that CT-0508, a CAR-M therapy targeting HER2-overexpressing tumors, successfully trafficked to the tumor microenvironment, promoted immune cell recruitment and upregulated antigen presentation,” said UNC Lineberger’s Yara Abdou, MD, an assistant professor of medicine and breast cancer clinical trial program leader at UNC School of Medicine.
Abdou and Thomas Condamine, PhD, of Charisma Therapeutics are the study’s corresponding last authors. Kim A. Reiss, MD, and Mathew G. Angelos, MD, PhD, of the University of Pennsylvania Abramson Cancer Center, Philadelphia, are the first authors.
The study enrolled 16 patients who had recurrent or metastatic solid tumors that overexpressed the HER2 protein and had not responded to standard treatments, including chemotherapy, immunotherapy or radiation therapy. Two patients withdrew from the study before receiving the infusion; one due to clinical deterioration and the other due to disease progression.
In some patients with high HER2 levels, tumor growth temporarily stopped, suggesting that antigen density plays a crucial role in therapeutic efficacy. The treatment’s effects were not sustained, however. Researchers also found that CAR-Ms could promote a more inflammatory tumor environment and enhance endogenous T-cell responses, suggesting the potential for combination therapies to improve long-term outcomes.
Abdou said the study establishes proof of concept for CAR-M therapy and underscores the need for further research to enhance its durability and effectiveness.
“These findings suggest that future research should explore combination strategies. This could include pairing CAR-M with checkpoint inhibitors, such as pembrolizumab, to overcome T-cell exhaustion and enhance long-term efficacy,” Abdou said.
Authors and disclosures
A comprehensive listing of the study authors and conflicts of interest can be found on the journal’s website.
Charisma Therapeutics sponsored the clinical trial.