Inside March Biosciences' CD5-Targeting CAR-T Approach

A conversation between March Biosciences' Sarah Hein, Ph.D., and Life Science Connect's Jon O'Connell

Targeting T-cell markers with a CAR T cell therapy presents one obvious challenge. How do you stop your therapeutic cells from simply destroying each other?

To date, no T-cell therapies have been approved for T-cell malignancies, including T-cell lymphoma, in large part because of the fratricide issue. Unmet need is driving real urgency to develop alternative therapies for these diseases; T-cell lymphoma relapse is common and patients who relapse have limited treatment options and low survival odds.

Sarah Hein, CEO and cofounder of March Biosciences, says her company has found a way to harness the power of T-cell therapy without triggering fratricide. The clinical-stage company based in Houston is developing a unique CD5-targeting CAR-T therapy approach to treat T-cell lymphoma as well as T-cell acute lymphoblastic leukemia. The company's lead candidate, MB-105, now in Phase 2 for T-cell lymphoma, downregulates the CD5 marker.

We spoke with Hein about the science behind the approach, the manufacturing choices driving it, and what the path to potential approval looks like from here.

What does March’s data reveal about CD5 surface recycling kinetics, and how does your approach maintain CAR-T persistence while managing fratricide risk?

Hein: Fratricide, which occurs when CAR T cells attack each other rather than the tumor, is the central engineering challenge in CD5-targeting, and how you solve it shapes everything downstream.

It’s important to understand that we’re not actually masking the CD5 receptor. What’s happening is that the CAR folds over, binds the CD5 receptor, and drives the internalization and degradation of the CD5 receptor. The CAR T cells become functionally CD5-negative at the protein level.

This eliminates any possibility of fratricide without having to do additional manipulations and gene editing that could damage the cells.

Durable complete responses are the goal, but sustained T-cell depletion is a real consideration with CD5-targeting approaches. How is March thinking about the long-term immune health of patients, and what have early clinical findings informed about that balance?

Hein: It’s a question we think about carefully and one the whole field is still working through.

Depletion and lymphopenia are common side effects of all CAR-T therapies. They stem from direct effects of the CAR and the conditioning chemotherapy prior to infusion, and infections remain the largest non-cancer-related consideration across CAR-T therapies. The picture is further complicated by an indication where many of these patients start lymphopenic prior to the therapy itself.

Our first goal is to eliminate the T-cell lymphoma, which is quite urgent in these patients. Following that, our clinicians have elected to do everything from waiting and monitoring to evaluating stem cell transplants as a means of reconstituting the immune system more quickly. This is all very much early days on best practices for management, but the important thing is to have the opportunity to get there.

Has March's self-elimination approach allowed for a shorter vein-to-vein time or more robust starting material compared to other T-cell lymphoma candidates?

Hein: There are many subtleties in manufacturing processes, but fundamentally, what we don’t have to do is additional manipulations or gene edits, which could cause damage to the cell overall or off-target mutations from something like CRISPR-based CD5 target elimination.

This keeps our manufacturing process very streamlined, allows us to move forward with a more consistent process, and keeps the vein-to-vein time quite short.

March is doubling down on autologous while many companies turn their attention to allogeneic — in part because allogeneic means starting with healthy donor T cells. How does your engineering overcome the fitness issues and variability often seen in autologous T-cell lymphoma products?

Hein: Autologous products will always have variability because of the patient’s own immune system, patient-to-patient differences, and prior treatments. But despite that, what we see consistently is that autologous products are the most potent and effective products developed to date, and in an indication like T-cell lymphoma, which is notoriously difficult and refractory, we strongly believe it’s our obligation to create the best opportunity for both complete responses and durable responses for these patients.

Once we’ve established our efficacy and core CD5 platform, there is always the opportunity to move to new delivery chassis. We have evaluated both allogeneic approaches and in vivo approaches. Allogeneic has had a lot of challenges, including a heavier requirement for conditioning chemotherapy in what is already a very fragile patient population. In vivo is closest to our current approach, and our CD5.CAR design would uniquely enable the opportunity as it does not require that ex vivo gene editing to remove CD5.

March is using G-Rex to streamline manufacturing. Does this reflect a long-term strategy to eventually move to point-of-care manufacturing, or do you see G-Rex primarily as a tool to maximize throughput at a centralized facility?

Hein: Point-of-care manufacturing has been an area of interest since cell therapies first emerged. But the truth is, we know how to move products around, and shipping is not the major limitation. You can maintain far better control through centralized, or at least regionalized, manufacturing. That latter model may be where cell therapy lands eventually as the field scales, something like an Amazon hub-and-spoke approach, which is meaningfully different from truly point-of-care manufacturing.

G-Rex enables the product characteristics we want while keeping the manufacturing approach simpler. That said, we’re always looking at new technologies that can further enable automation and scalability.

MB-105 has received both RMAT and orphan drug status — designations that bring tailwinds but also heightened scrutiny. What are FDA's milestone expectations, and what is March doing to meet them on the path to commercialization?

Hein: The key thing that RMAT and orphan drug status allows you to do is have more frequent conversations with the FDA and bring them in as a genuine partner toward the path to approval, and hopefully reach patients who desperately need more options sooner. Accelerated approval does not mean rushed, and we are working with the agency to ensure a safe and efficacious product throughout development.

About The Expert:

Sarah Hein is CEO and cofounder of March Biosciences. Before March, she was the founding entrepreneur in residence for the Texas Medical Center Innovation Accelerator for Cancer Therapeutics. She also cofounded Courier Therapeutics, where she served as vice president of operations, and before that, served as director of research at Resonant Therapeutics. She received her Ph.D. in molecular biology from Baylor College of Medicine.