MT-302, a TROP2-targeting mRNA-based CAR therapy, has shown preclinical safety and efficacy signals in patients with metastatic epithelial tumors and the potential to change the treatment paradigm for this population, particularly for those with tumors that have historically expressed TROP2, according to Charlotte Lemech, MBBS.

Preclinical studies in human myeloid cells have demonstrated specific expression of CD89-based CARs upon delivery of CAR mRNA/LNP in vitro. Systemic mRNA/LNP delivery of the CD89-based CAR also showcased robust antitumor efficacy against several tumor antigens in xenograft mouse models of human breast cancer, ovarian cancer, and hepatocellular carcinoma.

The phase 1, first-in-human MYE Symphony trial (NCT05969041) is investigating MT-302 in adult patients with advanced or metastatic epithelial tumors.

 Coprimary end points include safety and tolerability, as well as establishing the maximum tolerated dose of MT-302.

“The MYE Symphony study is bringing a new technology into the clinic as a first-in-class study,” Lemech said in an interview with 

. “[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.”

In the interview, Lemech, who is the medical director of the Scientia Clinical Research Facility, as well as a medical oncologist at the Prince of Wales Hospital in Sydney, Australia, discussed the unique mechanism of action of MT-302, the aims of the MYE Symphony trial, and how MT-302 may change treatment paradigms across tumor types.

: What is the mechanism of action of MT-302, and what is the need for this type of therapy in patients with metastatic epithelial tumors?

: MT-302 is a first-in-class in vivo CAR therapy. It is given intravenously either every week or every fortnight, and the schedule is currently under exploration. It is a lipid nanoparticle encasing an mRNA. The mRNA codes for the CAR, which comprises a TROP2-binding protein attached to a CD89 protein. On the myeloid cells is a gamma chain that is within the immune system and [upon interaction with the CAR, activates the [cell]. The TROP2 [binder] then goes to the TROP2 expressed on the cancer and binds to the protein for the molecule to then exert its anticancer effect based on activating the myeloid cells within the immune system.

Several treatments are available for epithelial tumors, and recent therapies have targeted TROP2 across many cancer types. 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.

How is MT-302 different from traditional CAR T-cell therapy?

For CAR T-cell therapy, it is cost-intensive and time-intensive to develop the CAR, and it is also intensive for the patient in terms of the lymphodepletion that is required before the CAR can be delivered. That’s specific to CAR T cells. [MT-302] is a CAR [myeloid] cell therapy. It does not require the lymphodepletion that is required for CAR T-cell therapy, and as such, can be given off the shelf [with] a marked reduction in time and potential toxicity for the patient.

What early research has been conducted with this mRNA CAR?

Preclinical data in several epithelial tumor types that express TROP2 have shown promising efficacy signals. The safety profile preclinically also looked reasonable. [MT-302 is associated with] the types of adverse effects [AEs] related to any agent that can boost the immune system that we have to monitor for, particularly cytokine release syndrome [CRS], which is seen with CAR T cells, as well as other immune-related AEs that might affect any organ. [The MYE Symphony] trial is currently in dose escalation, and we’ve cleared several dose levels so far. Further escalation and [safety testing] are ongoing.

How is the MYE Symphony trial designed, and what are its eligibility criteria?

MYE Symphony is a classic phase 1 trial. It’s currently in dose escalation through numerous dose levels, and there will be expansion based on the recommended phase 2 dose and efficacy signals that might be seen during escalation. The study is approximately halfway through the dose escalation. Backfill cohorts are ongoing based on some early efficacy signals that have been seen, which have been exciting.

The eligibility criteria are standard for a phase 1 trial. There are the criteria based on age, hematologic parameters, and biochemical parameters. There are also certain criteria to exclude patients who might be at greater risk of toxicity, such as if they have an autoimmune disease or have had toxicity, such as pneumonitis, with immunotherapy in the past.

The study also aims to enrich for tumors that historically have TROP2 expression demonstrated in the literature. This is not being tested prospectively but will be evaluated retrospectively in patients who are enrolled. The types of tumors of interest may be triple-negative breast cancer, hormone receptor–positive breast cancer, non–small cell lung cancer, genitourinary cancers, and some gynecological malignancies. A broad range of solid tumors are being considered for the study.

Paired biopsies are also required in this study; another eligibility criterion is that patients have a disease that is both measurable and able to be biopsied. [The trial is investigating] immune activation within the cancer cells themselves through those biopsies. There is a screening biopsy before the patient starts the study, and then an on-treatment biopsy after approximately 4 to 6 weeks on study.

A tricky part of these trials across antibody-drug conjugates and [drugs with] different mechanisms is that until the study is underway, you don’t know what level of TROP2 is required for [the drug’s] effect to be seen. We aim to focus on tumor types that have demonstrated TROP2 expression historically. However, it’s not a prospective test; patients [will not need to] have a certain level of TROP2 expression to come onto the study. [TROP2 expression] will be assessed retrospectively, as will other correlative studies evaluating different markers within the immune system.

Liquid biopsies are also being used, but the tumor tissue may give more in-depth information on some of the markers within the immune system.

How has MT-302 performed in MYE Symphony so far?

The patients coming on [the MYE Symphony trial] are all heavily pretreated, having exhausted standard lines of therapy. One of the difficult parts of phase 1 trials across the board is getting through some of the lower dose levels, which are selected based on the preclinical data. We need to start at a safe dose, but it is unknown when we will get to the dose where we see effects in patients. [There are questions regarding] whether modeling [the preclinical dose] translates [safely and effectively] into the clinical trial.

Additionally, the focus initially is safety. MT-302 is a first-in-class drug. The AEs [associated with] these types of immunotherapies can be significant, including CRS, which may lead to hospital admissions.

From that side, the safety so far has been as expected. There have been some CRS events in some of the patients, but these tend to be lower grade. We have seen a few patients who have had good signals of activity, which has led us to expand and enroll additional patients in those tumor types to explore further. Dose-escalation trials have small numbers to be able to comment on these signals, so it’s all preliminary data, but the dose-escalation plan has otherwise been continuing without any concerns regarding safety.

What are the protocol-mandated intervention strategies for some of these AEs?

There are a few mitigation strategies within the study. Firstly, all patients are kept overnight for their first dose on trial, as it is within that first day that you may expect to see CRS if it is going to occur. If there are any concerns after the first dose, patients can be kept overnight for subsequent doses if required. Usually, if they’ve gotten through the first dose, the likelihood of CRS with subsequent doses is lower. Premedications are defined within the protocol to reduce the risk of reactions. This is the standard protocol for the recommended management of CRS and what medications to use if it occurs.

Pending further positive data from the trial, how do you see MT-302 being integrated into current cancer treatment paradigms?

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 therapy. This is a step forward in getting an in vivo CAR into trials and the clinic. 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.

Argueta S, Melber FK, Gorgievski M, et al. 

 immune cell programming using mRNA-LNP chimeric antigen receptors. 

. 2024;84(suppl 6):1321. doi:10.1158-7445.AM2024-1321

Study of MT-302 in adults with advanced or metastatic epithelial tumors (MYE Symphony). ClinicalTrials.gov. Updated January 8, 2024. Accessed August 16, 2024. https://clinicaltrials.gov/study/NCT05969041

Articles

Charlotte Lemech, MBBS, discusses the mechanism of action of MT-302, as well as the aims of the MYE Symphony trial and its potential future implications.

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