MT-302 Utilizes Novel Mechanism of Action to Offer a Unique Treatment in Epithelial Tumors

Rasha Cosman, BSc, MBBS, FRACP

With the development of the novel in vivo chimeric antigen receptor (CAR) therapy MT-302, investigators are hoping to add an additional agent to the treatment landscape of epithelial tumors that has the potential to overcome the resistance mechanisms that are often acquired in heavily pretreated patients. The agent is currently under evaluation in patients with advanced or metastatic epithelial cancers in the phase 1 MYE Symphony study (NCT05969041).¹

“MT-302 is an innovative approach leveraging novel mRNAs wrapped in lipid nanoparticles delivered by standard intravenous [IV] infusion to reprogram the patient’s myeloid cells to seek and destroy TROP2 [trophoblast cell surface antigen 2]-expressing cancer cells and initiate a coordinated antitumor immune response,” Rasha Cosman, BSc, MBBS, FRACP, said in an interview with OncologyLive. “Due to the high prevalence of TROP2 expression in many different types of cancers, including lung, breast, gastrointestinal, [and] genitourinary, there is a potential to address unmet needs across a large population of patients. We see [TROP2] expression ranging from [approximately] 70% [of patients with] colorectal cancer, 90% [of patients with] ovarian cancer, and 85% [of patients with] hormone receptor [HR]–positive breast cancer.”

Cosman is the staff specialist and head of the Early Phase Clinical Trials Unit at The Kinghorn Cancer Centre of St Vincent’s Hospital in Sydney, Australia.

The mRNA lipid nanoparticles employed by MT-302 encode for a TROP2-targeted single-chain variable fragment fused to the transmembrane domain and cytoplasmic tail of CD89. The lipid nanoparticles are absorbed by multiple cell types; however, the CAR is only functional in myeloid cells, which provide an essential signaling component for signaling.²

“One of the novel aspects of this agent is that it is an in vivo CAR, and the intensity of the treatment is much less than that of historical CAR T-cell therapies. This is a step forward in getting an in vivo CAR into trials and the clinic,” Charlotte Lemech, MBBS, the medical director of Scientia Clinical Research, and a medical oncologist at the Prince of Wales Hospital in Sydney, Australia, explained in a separate interview with OncologyLive.

MT-302 Provides Proof of Concept for MYE Symphony With Strong Preclinical Data

MT-302 was evaluated in multiple preclinical studies. Argueta et al showed specific expression of the CAR encoded in MT-302 in myeloid cells in mouse and primate models after systemic delivery of mRNA lipid nanoparticles. The systemic delivery of the CAR via the mRNA lipid nanoparticles also displayed robust antitumor activity in xenograft mouse models of human breast and ovarian cancer. Syngeneic mouse tumor models also demonstrated antitumor immune responses with tumoral infiltration of activated CD8-positive T cells, reduced tumor-associated Tregs, systemically enhanced dendritic cells, and produced an antibody response against the tumor. The findings were presented during the 2024 American Association for Cancer Research (AACR) Annual Meeting.³

“We saw compelling efficacy in murine tumor models,” Cosman said. “[Additionally,], the expression and safety profile observed in non-human primates in 2 separate studies were very encouraging and support the clinical development of MT-302 in TROP2-expressing tumors.”

Lemech added that the preclinical safety profile of MT-302 appeared to be very reasonable. She noted that during MYE Symphony, investigators will have to monitor for immune-related adverse effects (AEs) commonly observed with CAR therapies, such as cytokine release syndrome (CRS), as well as other immune-related AEs that could affect any organs.

“Several treatments are available for epithelial tumors, and recent therapies have targeted TROP2 across many cancer types,” Lemech said. “However, once resistance develops to these therapies, there is an area of need for further novel drugs with new mechanisms of action that might overcome mechanisms of resistance to these other agents.”

MYE Symphony Is Set to Evaluate MT-302 in Epithelial Cancers

The multicenter, open-label MYE Symphony trial is the first-in-human study of MT-302 and is enrolling adult patients with advanced or metastatic epithelial cancer across 6 sites in Australia. The trial is enrolling approximately 48 patients with urothelial, cervical, ovarian epithelial, triple-negative breast, HR-positive/HER2-negative breast, non–small cell lung, or colorectal cancer, as well as those with pancreatic ductal adenocarcinoma, gastric adenocarcinoma, or esophageal carcinoma.^1,2

Other key inclusion criteria of MYE Symphony include patients having disease progression at baseline, relapsed/refractory disease to standard-of-care treatments, or declined standard therapy. Patients also need to have measurable disease per RECIST 1.1, an ECOG performance status of 1 or less, a life expectancy exceeding 12 weeks, and adequate organ function. Patients who have active central nervous system metastasis and/or carcinomatous meningitis, who are not more than 28 days beyond major surgery, and who previously underwent allogeneic bone marrow transplantation or solid organ transplant will not be eligible for the trial.

“The study also aims to enrich for tumors that historically have TROP2 expression demonstrated in the literature,” Lemech added. “This is not being tested prospectively but will be evaluated retrospectively in patients who are enrolled. The types of tumors of interest may be [TNBC], [HR]-positive breast cancer, non–small cell lung cancer, genitourinary cancers, and some gynecological malignancies.”

The coprimary end points of MYE Symphony are safety and tolerability and establishing the maximum tolerated dose of MT-302 based on dose-limiting toxicities and the recommended phase 2 dose. Secondary end points include pharmacokinetics, the rate of immune effector cell-associated neurotoxicity syndrome, and the rate of grade 3 to 5 CRS.

In September 2023, Myeloid Therapeutics announced that the first patient had been dosed with MT-302 in MYE Symphony. The study is currently recruiting patients, and the primary completion is estimated for August 2027.^1,4

“The MYE Symphony study is bringing a new technology into the clinic as a first-in-class study. [The trial and agent are] potentially relevant to a broad range of tumor types and target cancer in a different way that might overcome historical mechanisms of resistance,” Lemech said. “Based on what has been seen in this study with the safety and efficacy, it is early days, but there may be the potential to combine this type of agent with other therapies, such as checkpoint inhibitors, and move this type of treatment earlier into the treatment paradigm for several different cancer types.”

References

1. Study of MT-302 in adults with advanced or metastatic epithelial tumors (MYE Symphony). ClinicalTrials.gov. Updated January 18, 2024. Accessed October 29, 2024. https://clinicaltrials.gov/study/NCT05969041
2. Lemech C, Kichenadasse G, Teng C, et al. MYE Symphony: a first-in-human study to investigate the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the in vivo mRNA CAR therapy, MT-302, targeting TROP2 in adults with advanced epithelial tumors. Ann Oncol. 2024;35(suppl 2):S528. doi:10.1016/j.annonc.2024.08.742
3. Argueta S, Melber FK, Gorgievski M, et al. In vivo immune cell programming using mRNA-LNP chimeric antigen receptors. Cancer Res. 2024;84(suppl 6):1321. doi:10.1158/1538-7445.AM2024-1321
4. Myeloid Therapeutics initiates patient dosing with MT-302, a novel TROP2-targeting RNA CAR, in phase 1 study for advanced or metastatic epithelial tumors. News release. Myeloid Therapeutics Inc. September 12, 2023. Accessed October 30, 2024. https://myeloidtx.com/myeloid-therapeutics-initiates-patient-dosing-with-mt-302-a-novel-trop2-targeting-rna-car-in-phase-1-study-for-advanced-or-metastatic-epithelial-tumors/