New Gene Therapy Boosts Immune Reconstitution After Transplant


Alice Bertaina, MD, discussed combining T-allo10 gene therapy with stem cell transplants for the treatment of pediatric and young adult patients with hematologic malignancies.

Alice Bertaina, MD

Alice Bertaina, MD

Immune reconstitution posttransplant in pediatric and young adult patients with hematologic malignancies is suboptimal, and 25% to 30% of patients do not reconstitute as expected, putting them at risk of infection and leukemia recurrence. However, gene therapy with cell products have the potential to expedite the reconstitution process.

A phase 1/1b study (NCT04640987)combined a T-cell immunotherapy known as T-allo10, which is generated in vitro from donor CD4-positive T cells and enriched in type 1 regulatory cells, with the goal of suppressing host-reactive T cells that cause graft-vs-host disease (GVHD). Alice Bertaina, MD, presented findings from this study at the 2024 Transplantation and Cellular Therapy Tandem Meetings.

At the time of the data cutoff, 13 patients had been treated, and no dose-limiting toxicities were identified. The primary end point being evaluated was 50 CD4-positive T cells per microliter by day 60 posttransplant, which was met by 100% of patients.

The safety and efficacy of T-allo10 present significant advancements for improving outcomes of patients in the intent-to-treat population.

In an interview with Targeted OncologyTM, Bertaina, professor of pediatrics at Stanford School of Medicine and chief of the pediatric stem cell transplant program, discussed the study, its findings, and key implications for oncologists.

Multipotent stem cells in the bone marrow: © Juan Gärtner -

Multipotent stem cells in the bone marrow: © Juan Gärtner -

Targeted Oncology: Can you explain the rationale of the study?

Bertaina: The rationale lies in the observation that children and young adults are receiving the alpha beta T-cell-depleted haploidentical transplantation have a suboptimal immuno-constitution, especially in the early phases posttransplant. We know that at least the 25% to 30% of these patients are not reconstituting as we expect, which means they have a higher risk of developing infections and a higher risk of leukemia recurrence. We thought about developing a cell product which can fill this gap by expediting the immune reconstitution but not increasing the risk of graft-vs-host disease.

What are some of the unmet needs in this treatment space?

This protocol is targeted for pediatric patients and young adults with hematological malignancies, so mostly acute lymphoblastic [and] acute myeloid leukemia and myelodysplastic syndrome. These are diseases that when high-risk or relapsed after the first treatment have poor outcomesfor which only stem cell transplantation can be a curative therapy. With the advent of CAR T cells, ALL patients have a lot of options available. But this is not the same for AML or MDS. Even in the ALL field, there is a portion of patients who remain refractory or for which a transplant is necessary to consolidate the remission after the CAR T-cell therapy. This protocol, this approach, targeted the very high-risk population, which without a transplant cannot be cured, and is optimizing the outcome that the transplant itself can give.

What were the objectives of the study?

This study is a phase 1/1b trial. The first portion of the study has the goal of identifying the recommended dose for phase 2 of the trial. We have evaluated 3 escalating doses of the cell therapy. We have treated, so far, 13 patients, and we are now going to enroll 6 more patients to complete the identification of the dose.

In the phase 1 portion of the study, we had safety, and we didn't have any issue with safety. We didn't have any [dose-limiting toxicities] in any of the patients’ data so far, but also efficacy.Because our need is to improve the immune reconstitution to then improve leukemia recurrence and infection, we put as an end point that reaching a threshold of 50 CD4[-positive Tcells] per microliter by day 60. Why that? We know that patients will actually achieve 50 CD4 per microliter by day 100. In the context of T-cell-replete transplant and cord blood transplant, [we] have a much better outcome because they have a lower nonrelapse mortality, a lower risk of infection of relapse, and ultimately a better overall survival. We challenged that end point, and we decided to move it closer to the 60 days in our historical control. The percentage of patients reaching that goal was only 30%. We see in our 13 patients already that we have a statistically significant increase of a CD4 constitution by day 60, so we are excited that our hypotheses can be proven.

Can you summarize your findings?

First, no patients transplanted so far with this approach had transplant-related mortality, which is absolutely excellent considering the very high-risk population that we are treating in the first cohort. We even had 3 patients who received this transplant as a second transplant.Second, in the patients treated at the intermediate and high dose of T-allo10 cells, we have a 2-year leukemia-free survival and GVHD-free, relapse-free survival of 100%, which means that all those patients at 1 year after the transplant are alive, disease-free without having severe acute GVHD or chronic graft-vs-host disease.

One of our hypotheses was really the that the tier 1 enrichment of the T-allo10 cell product is the key ingredient and could have been traced and make sure that it persists in the recipient. Our findings show that shortly after infusion, we have an expansion of this tier 1 population, which reached a peak between day 1 and day 7 up to 20%, but then they persist longer. In the longer follow-up, we see a significant improvement in terms of CD4 immune reconstitution, which is especially into the memory compartment, but it's contributing also to the naive immune reconstitution, which is, again, a second additional step. We think that the infusion of the cells can also drive endogenous thymopoiesis.

We see a trend in improvement in terms of viral infection. In patients in cohort 2 and cohort 3 specifically, we see a reduced frequency of viral infections in comparison with historical control, especially for [cytomegalovirus] and adenovirus.

What are the key takeaways for a community oncologist?

I think that the main takeaway is that if we can utilize, if we can combine with a transplant a donor-derived cell product which is not going to cause graft-vs-host disease, we can quickly improve the immune reconstitution and have a much better long-term control of the disease. Obviously, this is a product that will be followed up with many more patients and with a longer follow-up. I think that the key message that is coming up is that this a product which is safe, and so if we can combine the properties of effector cells with regulatory T cells, we might have an ideal graft and post graft cell therapy that can improve survival.

Bertaina A, Packard L, et al. Enhanced immune reconstitution and reduced GvHD risk with T-allo10 infusion post Aβdepleted-HSCT in pediatric and young adult patients with hematologic malignancies Presented at: 2024 Transplantation and Cellular Therapies Meeting; San Antonio, TX; February 21-24, 2024. Abstract 16.
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