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).

“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 

. “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.

“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 

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.

“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.

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.

“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.”

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

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. 

. 2024;35(suppl 2):S528. doi:10.1016/j.annonc.2024.08.742

Argueta S, Melber FK, Gorgievski M, et al. In vivo immune cell programming using mRNA-LNP chimeric antigen receptors. 

. 2024;84(suppl 6):1321. doi:10.1158/1538-7445.AM2024-1321

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/

Articles

MT-302, a novel in vivo chimeric antigen receptor (CAR) therapy, is being evaluated for its potential to address resistance in epithelial tumors by targeting TROP2-expressing cancer cells. The MYE Symphony trial, a phase 1 study, is assessing MT-302's safety, tolerability, and efficacy in patients with advanced or metastatic epithelial cancers. Preclinical studies have shown promising antitumor activity and a reasonable safety profile. The trial aims to establish the maximum tolerated dose and explore the potential for combining MT-302 with other therapies.

Rasha Cosman, BSc, MBBS, FRACP, and Charlotte Lemech, MBBS, discuss the phase 1 MYE Symphony study (NCT05969041) of MT-302 in advanced or metastatic epithelial cancers.

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

Dr Cosman on the Potential Utility of MT-302 in TROP-2–Expressing Epithelial Cancers

Rasha Cosman, BSc, MBBS, FRACP, staff specialist, head, Early Phase Clinical Trials Unit, Kinghorn Cancer Centre, St Vincent’s Hospital; conjoint senior lecturer, University of New South Wales (UNSW), discusses the unique mechanism of action of the novel in vivo mRNA CAR therapy MT-302, highlighting its potential role in the treatment of patients with TROP-2–expressing epithelial cancers.

MT-302 is an innovative therapeutic leveraging novel mRNAs wrapped in lipid nanoparticles delivered by standard intravenous infusions to specifically reprogram a patient’s myeloid cells, Cosman begins. This therapy is designed to target TROP-2, a protein commonly overexpressed in various epithelial tumors, she notes. By harnessing the power of these reprogrammed cells, MT-302 aims to initiate a comprehensive antitumor immune response by infiltrating the tumor microenvironment and attacking cancer cells, Cosman explains.

The phase 1 MYE Symphony trial (NCT05969041) is a first-in-class study which is evaluating the novel CAR-myeloid (CAR-M) therapy in patients with advanced epithelial cancers that exhibit high TROP-2 expression, Cosman states. This phase 1 trial is primarily focused on establishing safety, determining the maximum-tolerated dose, and identifying the recommended phase 2 dose of the agent. Key secondary end points include evaluating the pharmacokinetics of the therapy and monitoring for immune-related adverse effects. Exploratory end points include assessing the therapy’s efficacy, as measured by overall response rate and duration of response. Additionally, the trial will examine the immunologic effects of treatment, looking at factors like peripheral CAR expression, cytokine release, and T-cell receptor clonality, as well as changes in the tumor immune environment and TROP-2 expression.

Three dose level cohorts have already been enrolled, and early signals of activity are promising, Cosman reports. If MT-302 is proven to be safe and effective, it could become an important therapeutic option for patients with TROP-2–expressing epithelial cancers, potentially overcoming many of the challenges experienced with ex vivo CAR therapies, she concludes.

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Rasha Cosman, BSc, MBBS, FRACP, discusses the mechanism of action and potential role for the in vivo mRNA CAR therapy MT-302 in TROP-2–expressing epithelial cancers.
 

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

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.

Research Efforts Are Underway in Advanced or Metastatic Epithelial Tumors | Supplements and Featured Publications

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

Dr Cosman on the Potential Utility of MT-302 in TROP-2–Expressing Epithelial Cancers

MT-302 Under Investigation in Advanced or Metastatic Epithelial Tumors