Early data from CAR macrophage trial show cell therapy is safe, feasible for solid tumors
Click Here to Manage Email Alerts
Three patients have been safely treated with CT-0508, a novel cell-based therapy, according to initial results of a phase 1 trial presented at Society for the Immunotherapy of Cancer Annual Meeting.
CT-0508 (Carisma Therapeutics) is an autologous, gene-edited chimeric antigen receptor macrophage therapy that targets the HER2 protein in tumor cells.
The characteristics of macrophages and how they engage with tumors differs from that of T cells, which makes CAR macrophage therapy “a different modality” than CAR T cells, Kim A. Reiss, MD, assistant professor of medicine in the division of hematology/oncology at Perelman School of Medicine at University of Pennsylvania, told Healio.
“CAR [macrophage] cells are highly present in the tumor microenvironment, and this particular product takes advantage of unique macrophage capabilities,” Reiss said. “These include tumor infiltration, phagocytosis and direct cytotoxicity, induction of T-cell recruitment and antigen presentation.”
Carisma Therapeutics and University of Pennsylvania collaborated to develop the technology, which capitalizes on previous cell therapies by using monocyte-derived macrophages genetically modified to express a CAR. Macrophages are naturally drawn into solid tissues and help modulate the tumor microenvironment, Reiss said.
“Really strong preclinical data” generated by the laboratory of Saar I. Gill, MD, PhD, at University of Pennsylvania formed the basic science research, Reiss said.
“They showed that CAR macrophages were able to exert targeted phagocytosis, as well as remodel the tumor microenvironment by inducing inflammation and recruiting T cells,” she added. “They primed an adaptive antitumor immune response by presenting antigen and activating antitumor T cells.”
Reiss presented data on the first two patients treated with the investigational therapy. She told Healio that a third patient not included in those results had been successfully treated with no serious treatment-related toxicities to date.
CT-0508 is being evaluated as part of a first-in-human multicenter study that includes patients with recurrent or metastatic HER2-positive solid tumors. Safety and manufacturing feasibility are the study’s primary objectives, with measures of efficacy and cell kinetics serving as secondary objectives.
Study patients received four doses of filgrastim to mobilize monocytes prior to apheresis. The manufacturing process takes 1 week and the total time from apheresis to final product infusion is 3 weeks, according to investigators.
The first patient treated with CT-0508 — a 72-year-old man with esophageal adenocarcinoma — had grade 4 tumor bleeding unrelated to the study therapy. The patient experienced disease progression after treatment.
The second patient — a 68-year-old woman — had stable disease after therapy. She developed grade 3 cytokine release syndrome on day 3 after infusion but it subsided the same day.
The lack of serious treatment-related adverse events among the first three patients and the lack of dose-limiting toxicities will allow the investigators to adjust the trial protocol “for ease of use and patient convenience,” Reiss said.
The initial trial protocol required the first three patients to receive a series of three doses with immediate hospitalization and observation for a prescribed number of days.
“The next move is to start doing this in the outpatient setting, with a brief observation period the day of infusion, and then the patients will be able to go home,” Reiss said.
Planned enrollment for the study is 18 patients, nine of whom will receive the treatment as one intravenous bolus dose.
The results reported at the SITC Annual Meeting were “very early, very preliminary” Reiss said, so it is too early to make any determination about the efficacy or durability of the treatment.
“Feasibility is the number one issue with this study because nobody has ever done this in humans,” she told Healio. “What we have learned from these first two — now three — patients is that this is a feasible approach.”
Analysis of the first two patients’ final manufactured product suggests that, after thawing, the CAR macrophage cells had “incredibly high” transduction levels, viability and purity, Reiss said. The safety results so far are just as encouraging, with a lack of severe or unexpected treatment-related toxicities, she added.
“This gives us hope that we can continue this trial safely and treat more patients,” Reiss said.
Perspective
Back to Top
Ecaterina E. Dumbrava, MD
Autologous cell therapies have been successful in hematologic malignancies, but efficacy in solid tumors remains disappointing. There are several possible mechanisms of resistance. These include identification and heterogeneity of an appropriate tumor antigen, and impaired T-cell trafficking and infiltration into the tumor tissue.
HER2 overexpression and amplification is a proven prognostic and predictive biomarker. Many HER2-targeted treatments are approved for breast and gastric cancers, and they are in development for other tumor types. Given its tumor cell specificity, HER2 is a favorite antigen for many cellular therapies in development.
To overcome the challenges with autologous T-cell therapies, which can have difficulty penetrating the tumor microenvironment, macrophages are naturally actively recruited from blood into tumors.
CT-0508 is an autologous, peripheral blood monocyte-derived, proinflammatory macrophage in proinflammatory M1 phenotype, transduced with an adenoviral vector containing an anti-HER2 CAR.
Reiss and colleagues report the preliminary results of treatment with CT-0508 in the first two patients treated in the study — one with esophageal adenocarcinoma and the other with cholangiocarcinoma. Both were HER2-positive and received prior treatment with trastuzumab (Herceptin, Genentech). Although these results are too early to draw any conclusions about the safety, tolerability or antitumor efficacy, they showed the CAR-engineered macrophages rapidly migrate out of the blood and lead to transient elevation of proinflammatory cytokines and intratumoral CD8-positive T-cell expansion and activation.
CAR macrophage therapy seems a promising approach to reach tumor cells, engage with the adaptive immune system and shift the tumor microenvironment toward tumor rejection. However, it has its own challenges, starting with transduction efficacy. The delivery rate of CAR macrophage cells to tumors also is an issue because macrophages, when compared with T cells, will not proliferate and expand in vivo after infusion. Finally, as CAR macrophages pass through the lungs, they might cause off-tumor, on-target respiratory toxicity.
This pivotal phase 1 clinical trial hopefully will answer many of these questions and will help us learn how to safely drive CAR macrophages toward efficient antitumor activity.
Collapse
Reiss KA, et al. Abstract 951. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 10-14, 2021; Washington, D.C.
Click Here to Manage Email Alerts