From November 14th to 17th, 2024, the Cellular Therapy and Immunotherapy Conference (CTI) was grandly held in Hangzhou, China, gathering top experts, scholars, and industry leaders in the field of global cell therapy and immune therapy. The conference served not only as an international platform for academic exchange but also as an important window to showcase the latest scientific research and promote the development of the field. During the conference, "Hematology Frontier" specially invited Dr. Marion Subklewe from the LMU University Hospital , Germany, to share with us the principles, advantages of AdCAR-T cell technology, and the future optimization direction of AML treatment.

Hematology Frontier：What are the main advantages of Adapter CAR-T (AdCAR-T) technology in the treatment of acute myeloid leukemia (AML)? How does it overcome the limitations of traditional CAR-T therapy?

Dr. Marion Subklewe ：So what we have observed so far in CAR-T cell trials, in the context of

AML, is a high incidence of severe cytokine release syndrome. Our approach using Adapter CAR-T (AdCAR-T) cells will increase the safety of CAR-T cells. These adapter molecules are small. They have a molecular weight of about 52 kilo Daltons. They are given as a continuous infusion, and their half-life is about 30 minutes.If you encounter higher-grade toxicity, you can stop the infusion of the adapter molecule, which is given as a continuous infusion similar to some of the bio-specifics, and thereby hopefully revert and stop the side effects.This is clearly one of the advantages of Adapter CAR-T (AdCAR-T) cells.

Currently, if you look at clinical government trials, most of the target antigens in the context of AML are CD33, CD123, and CLL-1. So, almost 90% of the clinical trials are following these myeloid lineage antigens. These have the expected on-target toxicity on the healthy hematopoietic system and are therefore mainly done as a bridge to transplant strategy. In contrast, CD7 is a more unique target antigen that is not expressed within the healthy hematopoietic system and is therefore more specific. It is expressed in about 30% of AML patients and has been presented and published in interesting data in the New England Journal of Medicine, where patients were treated with donor-derived CD7 CAR-T cells, followed by allogeneic stem cell transplantation. These patients accept lymphoid depletion did not really need conditioning or graft-versus-host prophylaxis. This seems to be a very interesting approach. However, what has also been seen is CD7 antigen loss and relapse. So, I think we probably need to target multiple antigens to be successful. Otherwise, we’ll always see antigen escape.

Hematology Frontier：How does AdCAR-T effectively target the heterogeneity of AML cells ? How has this strategy performed in actual clinical applications?

Dr. Marion Subklewe ：We know in AML that the target antigen expression is very heterogeneous, both inter- and intra-individuals. Even patients have different clones with different expression profiles of the same target antigen. So that’s very different from the CD19 CAR-T cell field.I don’t believe we can cure AML by targeting only one antigen with the adapter approach, where we have a generic CAR-T cell. The specificity is only given by the adapter molecule. We can exchange the adapter and thereby target multiple antigens, either in parallel or sequentially. So I think the big advantage of the adapter platform is that we can target multiple antigens.

Hematology Frontier：In optimizing CAR-T cell therapy strategies for acute myeloid leukemia (AML), what key factors do you believe need to be comprehensively examined and considered?

Dr. Marion Subklewe ：I think four aspects have to be considered to improve CAR-T cells strategies, or therapy in AML. First of all, we are currently using CAR-T cells in heavily pretreated patients after three or four prior treatment lines. I think we have to move bio-specific CAR-T cells、CAR-NK cells into earlier treatment lines with low disease burden. Second, I think we need to integrate targeting of multiple antigens. We’ll see antigen escape variants. So I think targeting two or three target antigens will be more successful. Thirdly, I think, as there is an immunosuppressive microenvironment and a recent report that also T cells secrete cytokines that mediate resistance of AML cells,that has been published in Nature Medicine, we also need to combine, for example, with JAK inhibitors or other small molecules to overcome resistance. And fourthly, other strategies like combining it with strategies of innate immunity like STING agonists could be really promising.

I think currently, our strategy, which is now independent of CAR-T cells, is very much focused on two aspects. The genetics of AML is very heterogeneous, and we have some targeted therapies, but it’s also prognostic. So we are looking at all the different genetic types. The second really important aspect is MRD, so MRD response, MRD persistence, or turning MRD positive again.

But I think in the context of immunotherapy, particularly CAR-T cells, we have to integrate the tumor microenvironment, sort of the health of the bone marrow as a third factor. Unfortunately, it’s gonna get more and more complicated with different small risk groups. I’m concerned that this will not be very attractive for industry, because we have really small patient population,if you stratify for genetics, MRD, and the microenvironment. So I think it’s really the task of academic medicine to propagate and develop AML specific CAR-T cells. Unfortunately, but I think, like everywhere in oncology, this has to be a personalized approach, although the patient numbers will get really small. But I think one-size-fits-all concepts are not going to work.

Hematology Frontier：Could you share what the biggest challenge you faced during your research was? And what are your expectations for future research directions?

Dr. Marion Subklewe ：There are two strategies currently being followed in AML. One strategy is applying CAR-T cells, achieving a morphological leukemia-free state, preferentially MRD negative, and followed by an allogeneic stem cell transplantation.And with this approach, you eliminate all the CAR-T cells. You only have the efficacy of the CAR-T cells for a very limited approach.But at least you can target myeloid antigens. And aplasia is not an issue. I think a very interesting evolving strategy is to do edited stem cell grafts. You delete sort of the target antigen by CRISPR/Cas, either the entire target antigen or by creating a non-synonymous mutation, just the epitope that is targeted, followed by CAR-T cells. And there you have the advantage. The CAR-T cells are allowed to persist. They have longer activities. So we’ll see how this turns out. And currently, we have no clinical trial data for the second approach yet.

One of the major challenges, in particularly in the context of acute myeloid leukemia, is identifying a suitable target antigen. As you are aware, most of the target antigens currently being employed are myeloid lineage antigens. There’s a great concern of on-target of leukemia, toxicity on the healthy hemorrhagic system, as you’re aware, and some malignancies. This is less of an issue because we can live without b cells and substitute IgG deficiency with IgG replacement therapy. So that is not the case with a myeloid compartment. Identifying suitable target antigen in AML is one of the challenges. The second challenge is that we have more resistance. It’s more like a solid tumor with an immunosuppressive microenvironment. These are the two challenges we address in AML.

I think besides target antigens and toxicity, another big issue in CAR-T cells and AML is resistance, mediated through the microenvironment and through T-cell, AML interaction. I think future strategies have to implement possibly other small molecules or conditioning regimens to counteract the immunosuppressive microenvironment. I think we will not be able to cure with just a CAR-T cell therapy, but need to adopt combinatory approaches. So, I think this is one of the future challenges we have to tackle.