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Conference Coverage

The “ABCs” of Immunotherapy for Patients With Acute Myeloid Leukemia


At the 2024 Annual Society of Hematologic Oncology (SOHO) meeting, Marion Subklewe, MD, Ludwig Maximilian University, Munich, Germany, discussed the current landscape and future development of immune and cellular therapies in acute myeloid leukemia (AML) research.

“[There is] lots of clinical development so far, [but] I think we still have to be patient,” concluded Dr Subklewe.

Transcript:

Hello, my name is Marion Subklewe. I work at the Department of Hematology Oncology at the [Ludwig Maximilian University] in Munich, [Germany] where I'm heading the section of cellular immunotherapy. Currently I'm in Houston at the [Society of Hematology] 2024 meeting where I gave an overview on immune and cellular therapies in acute myeloid leukemia (AML). It’s going to be the “ABCs” of immunotherapy in AML.

The ‘A’ stands for antibodies. Within the talk, I also try to highlight where we stand in clinical development. When we talk of antibodies, I like to highlight that antibody drug conjugates are the only immunotherapy platform that is currently being approved in AML. Namely [gemtuzumab ozogamicin] is the only approved immunotherapy in AML. As you know, it's a CD33-directed [antibody–drug conjugate] (ADC) approved based on the ALPHA trial. Within my talks talking about clinical development, I highlighted that there are currently other ADCs infusion proteins in clinical development.

I highlighted 2 agents, pivekimab, directed against 123 in ADC, that is currently being tested in frontline AML in conjunction with [venetoclax-azacitidine]. First data looks interesting with 78% [composite complete response] (CCR) rate and [a] similarly high rate of [measurable residual disease] (MRD) negativity. That will be interesting to watch as well as tagraxofusp. As you're aware, [it is] approved [for] (blastic plasmacytoid dendritic cell neoplasm) BPDCN, [and] it's now also being tested in conjunction with [venetoclax-azacitidine] in newly diagnosed AML. I found that trial interesting because it's only testing currently in an adverse genetic risk group. Preliminary data that was presented showed [an] interesting response rate. I'd like to highlight that half of these patients were [T]P53 mutated, [so] something to be watched.

[The] ‘A’ also [stands for] monoclonal antibodies. Some of these have reached phase 3 trials and unfortunately these failed to show a benefit. One trial concept integrated TIM-3 antibodies, nivolumab in high risk [myelodysplastic syndrome] (MDS) in conjunction with azacitidine failed to show a benefit. [There were] similar [complete response] (CR) rates, although there was a prolongation [of] duration of response. That trial was terminated in the program from Novartis due to futility.

Then we had the 2 phase 3 trials integrating the high affinity anti-CD47 antibody magrolimab, which had been tested in the [ ] [phase] 2 and 3 trial with TP53-mutated and also elderly unfit AML patients. Both trials were terminated, and the program closed due to futility. One of the obstacles has been phagocytic anemia due to magrolimab. We'll see how other monoclonals will develop. But my conclusion, particularly to the monoclonal antibodies, is, it's probably naive to think 1 antibody fits all. I think we have to increase our biomarker program to better identify patients that are likely to benefit from these reagents.

In our ABCs of immunotherapy, we'll move on to bispecifics. I gave an overview on the clinical trials that have been conducted in that setting. Across trials independent of the target antigens, which are mainly CD33, [ ] and CD123, the most common adverse event is cytokine release syndrome (CRS). That led to almost all trials to implementation of dose steps, and that led to protracted patient [ ] and difficulties to reach the final target dose. Unfortunately, in most of these trials, overall response rates (ORR) were rather disappointing. They were reported up to 50%.

I'd like to highlight 4 different strategies that are currently being employed to improve efficacy and that are currently running in early phase 1/2 trials. [The first strategy is] integration of multi-specific antibodies, but also antibodies targeting intracellular antigens that are presented in the context of (major histocompatibility complex) MHC molecules, thereby decreasing on target of leukemia toxicity and overcoming some of the obstacles. Second, [the] integration of a positive [ ], either [ ] or by applying another bispecific to increase T-cell fitness and thereby maybe overcoming [an] immunosuppressive tumor microenvironment. Third, using it in combination therapy. [There is] interesting preclinical data from our lab has been generated in conjunction with [venetoclax-azacitidine], which doesn't seem to have a negative effect on T-cells. So, there might be a benefit in combination. And fourth, using bispecifics in low disease burden, preferentially [in the] MRD-positive setting. I'm happy that several trials are currently recruiting patients into trials where MRD-positive patients are integrated.

Let's move on to the ‘C’ [in the ABCs]. I would like to summarize the different strategies that are currently employed of utilizing (chimeric antigen receptor) CAR T-cells. In AML, the most common strategy here is a bridge-to-transplant strategy. Here, the aim is to achieve a morphological leukemia- free state, preferentially MRD-negative. Then, the T-cells, or the adoptively transferred CAR T-cells, are eliminated with the conditioning, and a salvage transplant can be done. Several small trials have reported their results. Clearly one can say proof of concept has been shown. Some of these trials have reached high MRD-negativity, but across trials, I would say 30% to 50% of their trials [that] achieved MRD-negativity in patients successively went on to transplant.

However, long-term follow-up is missing, so the benefit long-term is less clear. The second strategy [is] interesting and based on novel technologies is utilizing an edited stem cell graft followed by CAR T-cells. The stem cells become invisible to the then later adoptively transferred, for example, CAR T-cells. This is feasible [and] has been shown with the CD33-deleted hematopoietic stem cell graft, 3 patients have [ ] reconstituted their cells. In this trial, gemtuzumab was given after recovery of [ ], [with] no cytopenias [being] observed and now [with] more advanced technology being applied. (Clustered regularly interspaced short palindromic repeats) CRISPR-based editing of the stem cell graft through integration of non-anonymous mutation, the epitope that is recognized by the CAR T-cells, is deleted. Then you can adopt a [ ] transfer and that has been shown preclinically CD45 or FLT3, CD123, and C-Kit specific CAR T-cells. Hopefully, these sort of fancy concepts will enter clinical trials in 2025. And lastly, 1 strategy is trying to do CAR T-cell [therapy] without an allogeneic stem cell transplant. These are selectivity enhanced CAR T-cells and their dual CAR T-cells as well as adapter CAR T-cells are being followed. [Currently] patients [are being] recruited into early clinical trials.

This was my summary of the ABCs of immunotherapy and AML. [There is] lots of clinical development so far, [but] I think we still have to be patient. There are 2 messages that are important to me moving forward. I think we have to increase the biomarker program, harmonize our biomarker program and go beyond genetics and MRD and also integrate immune context, the tumor microenvironment as a possible important biomarker for immunotherapy studies. And second, we need to apply our immunotherapy strategies in early disease burden preferentially MRD, when there's a fitter T-cell compartment and more likelihood for responses in these patients. Thank you.


Source:

Subklewe M. Immune/cellular therapy in AML. Presented at the 2024 Society of Hematologic Oncology meeting. Houston, Texas; September 4-7, 2024.

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