Inside ImvivaBio's Trial For Off-The-Shelf CAR-T Strategy For Aggressive T-Cell Malignancies

A conversation between ImvivaBio CMO Jan Davidson-Moncada, MD, Ph.D., and Clinical Leader Executive Editor Abby Proch

Allogeneic CAR-T therapies hold promise as off-the-shelf options for patients with aggressive cancers, and ImvivaBio is hoping its CD7-targeting CAR-T candidate and supporting ANSWER™ (ANtibody SWitch Engineered Receptor) platform that reduces lymphodepletion burden will be just the thing patients need for quick, safe, and potentially curative treatment.

In this interview, Chief Medical Officer Jan Davidson-Moncada, MD, Ph.D., discusses CTD402, now advancing through the TENACITY-01 Phase 1b/2 study for relapsed or refractory (r/r) T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL).

He explains the unmet need in these aggressive malignancies, the rationale for an allogeneic approach, and how ImvivaBio’s ANSWER™ technology may help address immune rejection. He also shares perspectives on trial design, manufacturing scalability, global access, and where the company hopes to take CTD402 next.

Clinical Leader: What is the unmet need for the malignancies that support an off-the-shelf cell therapy as opposed to an autologous one?

Jan Davidson-Moncada, MD, Ph.D.: The CD7-targeting CAR-T cell is being developed for r/r T-cell T-ALL/T-LBL. No drug has been approved in this space since 2005. Nelarabine was the last drug that was approved, and it has moderate  activity and a lot of toxicity.

Part of the reason that other CAR-T modalities are challenging for leukemia and lymphoma of T-cell origin is that the T-cell are the source of CAR-T. So, if you were to generate autologous CAR-T cells from the patient, it would be very difficult to tease out a good T-cell from a “bad” T-cell. On the same note, for in vivo CAR-T cells, a newer modality with a lot of promise, the source is the patients own T-cell but instead of producing them ex- vivo, we are just generating them in vivo-in the patient. So, we are administering something to the patient that will then get into their T-cells and make them CAR-T cells. It's going to be very difficult to generate a vector, either lipid nanoparticles or viruses, to differentiate between a non-malignant and a malignant T-cell.

In both cases there is risk of potentially making a malignant T-cell into a CAR-T, which could lead to further complications.

In terms of the underlying disease, the malignancy can be very, very aggressive. A lot of time, there isn't enough time to harvest the T-cells, manufacture them, get them ready, and pass all the clearances needed for administration in a timely manner. We know from B-cell ALL that about 10% to 15% of patients do not get their autologous CAR-T cells because the disease progresses beyond something that is salvageable with the CAR-T administration.

An off-the-shelf, point-of-care-ready product can be given just as soon as you identify the patient; the product is sitting in your minus 80-degree freezer, and it's ready to administer. It’s also better because some of these patients progress so rapidly that administering CAR-T cells too late may not be effective.

What timeframes or time savings are possible with CTD402?

Currently, because it's a clinical study, the cells are stored in a depot, and we ship the cells ready for the patient. But in the future, as soon as the patient is identified and conditioned, the drug is sitting there in your pharmacy. It wouldn't be any different than if you had a headache, you go to your medicine cabinet, and you take out ibuprofen.

When you were designing the trial for TENACITY-01, what choices did you hope would help generate data that would take you to the next phase?

We had about 100 patients' worth of data from our Chinese trials in which we had already established the safety, the efficacious dose, and the optimal lymphodepleting therapy when approached the FDA for our IND. Hence, in TENCITY-01 we confirmed safety and the efficacious dose and rapidly proceed towards Phase 2. Eventually, we'll launch the study in Europe as well as Australia and some other Asian countries such as Japan.

Does that mean you established your Phase 1 trial in China first before bringing Phase 2 to the U.S.?

All the early development was largely done there. We opened sites in China to test the different kinds of treatment paradigms and verify them. In those studies, saw that the product was well tolerated and active, with response rates of greater than 60%. And so, we felt comfortable bringing extending into the rest of the world.

One of the issues with allogeneic CAR-T cells is that the CAR-T itself is foreign to the recipient. And one of the biggest challenges is that when you administer the drug, the body fights, rejects, the actual CAR-T. What a lot of companies have done to mitigate that is increase the doses of immunosuppressant cytotoxic medication to the patient prior to giving the CAR-T to dampen the patient's immune system, so the CAR-T has time to expand and survive to eliminate the malignant cells; this, however, increases risk for the patient.

Through the development of CTD402 in China, we developed ANSWER™, antibody switch receptor technology. ANSWER™ works by paralyzing or stopping the immune response against the CAR-T cell without actually eliminating the patient's own immune system. And because it is so efficient in reducing immune rejection; hence, we use lower doses of lymphodepletion while achieving good CAR-T expansion and persistence. That is a lot safer for the patient, reducing treatment-related morbidity and mortality while not impacting efficacy.

Earlier in the conversation, you talked about a future where this therapy is available off-the-shelf. How viable is this from a manufacturing perspective?

From one donation, you can make infusions to treat 50 or so patients, and that's much different than the autologous product, which is a single product from the patient for that patient; this incurs cost and time. Whereas our CMC team can generate two or three of these batches from a single apheresis, and that's sufficient to supply the whole clinical study, which is aiming to treat about 100 to 120 patients.

Conceptually, when you get into trying to commercialize this, it's a lot more viable if you can manufacture in bulk.

We talked about patient accessibility and scalability in manufacturing as some commercial wins. Are there more?

There was a recent paper in Blood that talked about the availability of approved autologous CAR-T cells. There have been about seven approved CAR-T cells within the B-cell malignancy space. And if you look at where they're approved and where they can be received globally, the map looks sparse. There are not a lot of countries with access. If you're going to distribute this globally, you want to have a product that can be easily shipped and stored. That allows access in countries that don't have the infrastructure for apheresis collections and manufacturing. Many countries have to ship the source material, T-cells, back to the US or Europe for manufacturing.

Allogeneic CAR-Ts can be manufactured in a central location and then distributed for populations throughout the world. At the end of the day, diseases such as T-ALL are not confined to geographies where that infrastructure exists. These patients exist everywhere.

What are the patients potentially gaining over the current standard of care?

Nelarabine was approved with an approximate 20% response rate and a median duration of response of about two months. A lot of physicians actually opt not to use nelarabine due to moderate activity and toxicity, and hence instead give more cytotoxic chemotherapy. While these chemotherapeutic regimens are actually quite effective in the frontline setting, they are not as effective in second line because patients have essentially not responded to the initial, have progressed beyond, or relapsed after receiving chemotherapy. Cytotoxic chemotherapy is also tough to receive once, but it can be even tougher to receive a second, third, or fourth time.

With CTD402, patients can come in and receive a single infusion of a CAR-T and potentially very long remission, or a “cure”, especially when combined with a transplant. When combined with a transplant, we have seen patients who remain disease free well beyond three years.

What does the next year or so hold for ImvivaBio?

We're now launching a cohorts in the TENACITY-01 study to eradicate minimal residual disease. Even though there is a lot of interest in treating patient with minimal disease, nothing has been approved in this space except for blinatumomab. The arm is going to test whether a single infusion of CAR-T cell can turn these patients into MRD-negative status, which has been shown to confer a longer remission and much better benefit to the patients.

On top of that, we will be expanding the CTD402 program and testing it in other diseases, including, for example, CD7+ AML as well as non-malignant indications. There are some autoimmune diseases in which the pathogenesis is  T-cell driven. So, eradicating those T-cells will be a benefit for these other autoimmune indications.

In terms of TENACITY-01, we are in the midst of discussions with the FDA and hope to align with the agency towards a registration path.

About The Expert:

Jan Davidson-Moncada, MD, Ph.D., is the Chief Medical Officer at ImvivaBio. He is an NIH-trained hematologist and oncologist with 20+ years of academic and clinical experience in oncology drug development. He has experience across multiple modalities, including cell therapeutics, ADCs, immuno-oncology, and small molecules. Before joining ImvivaBio, he served in key clinical development and translational research roles at Wugen and MacroGenics. He earned his MBBS and Ph.D. in molecular medicine from University College London.