Cellular Therapies Hold Promise in Myeloid Malignancies

There is hope that these therapies will improve outcomes, but development is still in early stages. 

A recent spate of approvals of targeted treatments, such as FLT3 and IDH1/2 inhibitors for acute myeloid leukemia (AML), introduced major changes in the treatment of myeloid malignancies. Recently, across the spectrum of hematologic malignancies, cellular therapies are gaining traction. Now, as scientists better understand the biology of myeloid malignancies, cellular approaches are poised to overtake targeted treatments as the “next big thing” in myeloid malignancies.

Myeloid malignancies are clonal diseases of hematopoietic stem or progenitor cells that can be present in the bone marrow or peripheral blood. The term encompasses AML, myelodysplastic syndromes, myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasm overlap syndromes, and myeloid neoplasms associated with eosinophilia and abnormalities of growth factor receptors derived from platelets or fibroblasts.

Immune dysregulation is a central aspect of myeloid malignancies, making immune-based approaches to treatment appealing. Recently, with the success of chimeric antigen receptor (CAR) T-cell therapies in lymphocytic leukemia, lymphoma subtypes, and myeloma, researchers are hopeful that these new immunotherapeutic approaches can be harnessed in the treatment of myeloid malignancies.

“We need to learn more about why the immune system fails in myeloid malignancies,” said Saar I. Gill, MD, PhD, assistant professor of medicine at the Hospital of the University of Pennsylvania. “We do not have a good understanding of the mechanisms of defense that a disease like AML constructs around itself; knowing what these are will allow us to be more logical about applying available tools.”

ASH Clinical News spoke with Dr. Gill and other researchers and clinicians specializing in myeloid malignancies about the evolving role of cellular therapies in these diseases and the challenges that need to be overcome before they make it to the clinic.

Transplant: The Original Cell Therapy

Across the spectrum of myeloid malignancies, there is currently no drug therapy that can cure disease. A proportion of patients with AML can be cured with chemotherapy – mostly those with favorable or intermediate disease risk features. But the treatment with the best potential for long-term remission is allogeneic hematopoietic cell transplantation (alloHCT), noted Katy Rezvani, MD, PhD, of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center.

“Transplant is the main curative option for many patients with high-risk AML or relapsed or refractory AML,” she told ASH Clinical News. “At our center, AML is the main indication for alloHCT.”

Outcomes from transplant have improved during the last three decades, Dr. Rezvani noted, largely due to reductions in transplant-related mortality. “If you look at the relapse rate, though, particularly among patients with high-risk AML, it has not significantly changed over the last three decades,” she said.

In addition, many patients with AML will not qualify for transplant because of their age, lack of a matched donor, or other comorbidities.

“That is why a lot of effort is being put into novel treatment strategies,” Dr. Rezvani said.

In some cases, the new strategies being evaluated are looking at forms of maintenance therapy to help decrease risk for relapse after transplant. Other strategies are looking to harness immunotherapy and cellular therapies or to take advantage of the graft-versus-leukemia effect using donor lymphocyte infusions.

CAR T Cells

The U.S. Food and Drug Administration (FDA) approved the first cell-based gene therapy – tisagenlecleucel – in 2017 for certain pediatric and young adult patients with acute lymphocytic leukemia (ALL). One multicenter clinical trial of the treatment strategy showed an overall remission rate of 83% in patients with relapsed or refractory B-cell precursor ALL.1

In B-cell malignancies, CAR T-cell therapies are designed to target several antigens specific to B-cell lineage, such as CD19, CD20, or, in the case of myeloma, B-cell maturation antigen. According to Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch and the National Cancer Institute’s Center for Cancer Research, “we are trying to leverage the skill set launched from targeting B-cell malignancies and trying to apply that broadly to AML.”

Among several trials investigating this approach, enrollment has started on a multicenter phase I/II study of anti-CD33 CAR T-cell therapy in children and young adults with relapsed or refractory AML (NCT03971799).

“Based on the experience with effective antigen-targeted, antibody-based therapies in AML, there may be multiple antigens that are potentially amenable to targeting by T-cell–based therapies,” Dr. Shah said.

However, Dr. Gill warned that identifying a target in myeloid malignancies may not be straightforward. “We are testing CAR T cells directed against CD123 or CD33, for example, but those antigens are present at the same amount on malignant cells as they are on subsets of normal cells,” he said. “This is a very important limitation to CAR-based or bispecific T-cell engager approaches in myeloid malignancies because you have to expect profound and protracted depletion of normal myeloid cells in order to get profound and protracted depletion of malignant cells.”

Dr. Shah agreed that this on-target, off-tumor effect is a concern.

“The issue is that myeloid targeting can happen with abnormal myeloid cells, but also with hematopoietic precursor cells, and that is going to lead to intolerable toxicity,” Dr. Shah said. “For someone to develop aplasia of the myeloid line could be very problematic. It increases their risk of infection and they could become transfusion-dependent.”

This means that, as opposed to its “one-and-done” role in B-cell malignancies, CAR T-cell therapy may have to be used as a bridge to transplant in AML.

NK Cell Therapies

Another class of T-cell therapy entering the spotlight is natural killer (NK) cell therapy. These products offer a distinct advantage over allogeneic CAR T cells: They are much less selective. Unlike CAR T cells, NK cells do not require antigen-specific priming to launch an immune response against viruses and cancer. Thus, they can serve as an off-the-shelf source of cells for immunotherapy. In clinical trials, NK cell therapy has demonstrated less toxicity than CAR T cell products, including no instances of graft-versus-host disease.

“NK cells have the inherent ability to recognize and kill many cancers,” Dr. Rezvani said. “AML cells are particularly susceptible to NK-mediated killing because they express some of the ligands that NK-activating receptors recognize.”

In a study published in 2020, Dr. Rezvani and colleagues used NK cells to target lymphoid malignancies.2 Since lymphoid malignancies are less vulnerable to NK-mediated killing, Dr. Rezvani said the study used NK cells that have been engineered to express an anti-CD19 CAR – an approach that takes advantage of both T-cell therapies. Although it was a small study, investigators saw an outstanding safety profile with encouraging clinical responses. Of the 11 patients with relapsed or refractory CD19-positive cancers included in the trial, 73% had a response.

“When designing the study, we focused on CAR19-NK cells as proof-of-principle, in view of the impressive results reported in lymphoid malignancies with CAR19 T cells,” Dr. Rezvani said. “Now we are putting a lot of effort into targeting cancers that we know have susceptibility to NK-mediated killing.”

They are also trying to harness the power of CARs. “Even if not all the AML blasts express the antigen we are targeting with the CAR, let’s say CD123, then the blasts that are CD123-negative can still be recognized and killed by NK cells through their innate receptors,” she said.

While CAR NK cells are allogeneic and could be potentially manufactured in advance and stored off-the-shelf for immediate use, Dr. Rezvani noted that their trial in lymphoid malignancies used fresh rather than frozen CAR-NK cell product.

“If we want to reduce cost, we would need an off-the-shelf product manufactured in bulk that could be frozen and used to treat multiple patients,” she said. “We are working on this approach, but data with frozen NK cells are more limited.”

Engineered T Cell Receptors

An additional cellular therapy approach being explored in myeloid malignancies is the use of engineered T-cell receptors.

“Unlike with CAR, this approach allows you engineer the T cell to express the alpha and beta chains of a T-cell receptor that you know confers T cells with the ability to recognize a tumor-associated or tumor-specific intracellular antigen,” Dr. Gill said.

For example, a study by Aude G. Chapuis, MD, and colleagues published in 2019 used T-cell receptor gene therapy to target Wilms’ tumor antigen 1 (WT1).3 The researchers isolated a high-affinity WT1-specifc T-cell receptor from HLA-A2 positive normal donor repertoires and inserted it into Epstein-Barr virus−specific donor CD8-positive T cells. These were infused prophylactically post-transplantation into 12 patients with AML.

At a median of 44 months after the infusion, recurrence-free survival was 100%; recurrence-free survival in a comparator group was 54%.

“I was shocked at how clear these results were in the setting of relapse prevention,” Dr. Gill said. “In contrast, the approach did not appear successful in treating patients with active leukemia.”

The Limits of Cellular Therapy

Despite the recent advances in cellular therapies, many challenges remain in the treatment of patients with myeloid malignancies.

One obvious limitation to CAR T-cell therapy, according to Dr. Shah, lies in the unknowns of manufacturing CAR T cells from patients with AML. “We don’t know if the CAR T cells are going to be functional, or what levels of neurotoxicity or cytokine release syndrome we will see,” she said.

Dr. Rezvani agreed. “At the moment, the CAR T cells being used in clinical trials and approved by the FDA are autologous products,” she noted. “They are patient-specific and expensive because of the complexities of manufacturing.”

The cost and time challenges could be overcome with development of allogeneic products, but those approaches remain to be validated and made widely available across malignancies.

Another limitation to the development of CAR T cells in this setting is that AML is a fast-growing malignancy, said Dr. Gill.

“By the time patients with AML are enrolled in any early-phase clinical trial, they have been through a lot,” Dr. Gill explained. “They have likely been cytopenic for a long time and have a history of multiple infections or are at high risk for infection. With a high incidence of adverse events at baseline, this is a very difficult patient population to treat.”

More work is needed to identify targeted therapies – like FLT3 or IDH1/2 inhibitors – that can delay disease progression, Dr. Gill said.

“These therapies buy you time to get the patient onto a clinical trial or to manufacture CAR T cells,” he said. “Conceivably, they keep the patients stable for long enough to enjoy the benefit of cellular therapy.”

The biggest challenge, according to Dr. Gill, is understanding AML and finding a cancer-specific antigen – if there is one. “Otherwise, we are just hoping to stumble into something,” Dr. Gill said. “That is inefficient, costly, and disappointing.”

“For both CAR T cell and CAR NK cells, it is very likely that the next generation of products could lead to cure, especially if used earlier in the disease course,” Dr. Rezvani said, adding that this goal has already been achieved in certain trials. “If you look at the data for CAR T cells in non-Hodgkin lymphoma, about 55% of patients achieve complete remission, with many remaining in remission without the need for consolidation or a transplant.”

Dr. Rezvani said that although challenges remain, she is hopeful that they can be overcome, especially as the field becomes better at managing toxicities related to CAR T-cell therapies.—By Leah Lawrence


  1. U. S. Food and Drug Administration. FDA approval brings first gene therapy to the United States. August 30, 2017. Accessed March 24, 2021. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states.
  2. Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med.2020;382(6):545-553.
  3. Chapuis AG, Egan DN, Bar M, et al. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nat Med. 2019;25(7):1064-1072.