Researchers at Memorial Sloan Kettering Cancer Center (MSK) have now introduced an innovative CAR T cell therapy that distinguishes itself by targeting a protein uniquely expressed on the surface of leukemia cells but absent from healthy blood progenitors. This selectivity arises from exploiting a protein called U5 snRNP200, a component usually confined within the nucleus but intriguingly translocated to the cancer cell surface in nearly half of AML patients. The presence of this protein on the external membrane deviates from classical cell biology paradigms, opening a therapeutic window previously unrecognized.

The team’s approach leveraged antibodies derived from AML patients who had undergone bone marrow transplantation and experienced long-term remission. These antibodies, which naturally target the aberrant U5 snRNP200 expressing leukemia cells, provided the molecular blueprint to engineer chimeric antigen receptor (CAR) T cells. By integrating the precise antigen-binding domains of these antibodies, scientists created CAR T cells that mimic the body’s most effective immune response—the graft-versus-leukemia effect—without debilitating healthy hematopoiesis.

Operationalizing this discovery required sophisticated genetic engineering. The CAR T cells were “armored” by inserting genes encoding interleukin-18 (IL-18), a pro-inflammatory cytokine that enhances immune activation. IL-18 secretion serves a dual function: it not only amplifies the presentation of the U5 snRNP200 protein on leukemia surfaces by inducing cellular stress responses but also invigorates the broader immune microenvironment, potentiating more robust anti-leukemic effects. This dual mechanism addresses one of the limitations of conventional CAR T therapies—tumor antigen loss and immunosuppressive niches.

Preclinical trials using rigorous animal models demonstrated compelling efficacy. Mice harboring both adult and pediatric AML models showed complete remission after CAR T cell treatment, and, notably, they developed immunological memory capable of resisting leukemia reinfection almost a year later. Such durable immunity suggests these CAR T cells not only eradicate existing leukemia but also provide long-term surveillance against relapse, a crucial feature given AML’s notorious recurrence rates.

Beyond AML, these engineered CAR T cells proved effective against B-cell acute lymphoblastic leukemia (B-ALL), a distinct leukemia subtype characterized by the proliferation of immature B cells. Strikingly, around 90% of B-ALL samples expressed the U5 snRNP200 protein, validating this antigen as a versatile target across multiple blood cancers. Importantly, the therapy effectively targeted B-ALL cells resistant to current CD19-targeting CAR T cells, overcoming a key mechanism of treatment failure and relapse.

The discovery stems from a paradigm shift—rather than focusing solely on mechanisms causing treatment resistance, the research team sought to understand and harness what contributes to patient survival. By decoding the natural immune defenses of patients in remission, they designed a therapy that reproduces and augments nature’s most efficacious immunological responses. This biomimetic strategy represents a conceptual advance in cancer immunotherapy design.

Further strategic advantages of this method include the essential nature and intracellular origin of the U5 snRNP200 protein, which significantly reduces the likelihood of antigen escape mutants emerging—a common and serious challenge in CAR T cell therapies. Since the protein is vital for cellular survival and is typically intracellular, leukemia cells cannot simply downregulate its expression without compromising their viability, ensuring sustained therapeutic targeting.

Although these findings are preliminary and derived from animal models, the safety profile looks promising. By sparing normal hematopoietic progenitor cells and minimizing off-target effects, this approach could redefine the therapeutic index for aggressive leukemias. Researchers at MSK are now advancing preparations for an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA), a requisite phase before human clinical trials can commence.

Commercial and philanthropic partnerships are being sought to accelerate the pathway from bench to bedside. The translation of this therapy into clinical practice could ultimately improve the survival rates of AML patients, a population for whom only about 30% survive beyond five years post-diagnosis, underscoring the urgent need for novel, durable, and safer treatments.

Expert commentary from Dr. Anthony Daniyan, a lead investigator and hematologist at MSK, underscores the novelty and clinical promise of this therapy. Dr. Daniyan highlights the mystery around the anomalous surface localization of U5 snRNP200 and the ingenious way the team exploited this to overcome prior therapeutic barriers. Meanwhile, Dr. Omar Abdel-Wahab emphasizes the importance of deriving insights from successful patient outcomes, presenting a fresh perspective on tackling leukemia immunotherapy.

This breakthrough not only exemplifies next-generation cancer immunotherapy but also demonstrates the immense value of integrating immunology, molecular genetics, and clinical observation into a cohesive development process. The innovative CAR T cell therapy targeting a surface RNA-binding protein could revolutionize the management of aggressive blood cancers and inspire similar approaches across oncology.

Subject of Research: Development of CAR T cells targeting a surface RNA-binding protein for acute leukemias

Article Title: Development of CAR T cells Targeting a Surface RNA Binding Protein for the Treatment of Acute Leukemias

News Publication Date: April 30, 2026

Web References:

• Memorial Sloan Kettering Cancer Center: https://www.mskcc.org
• CAR T cell therapy info: https://www.mskcc.org/cancer-care/diagnosis-treatment/cancer-treatments/immunotherapy/car-cell-therapy
• Published study: https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-25-0920/784642/

References:

• Daniyan, A. et al. “Development of CAR T cells Targeting a Surface RNA Binding Protein for the Treatment of Acute Leukemias.” Cancer Discovery, April 30, 2026. DOI: 10.1158/2159-8290.CD-25-0920

Image Credits: Memorial Sloan Kettering Cancer Center

Keywords: Acute Myeloid Leukemia, CAR T cell therapy, Immunotherapy, U5 snRNP200, Leukemia, Cancer Discovery, Bone marrow transplantation, Graft-versus-leukemia effect, IL-18, B-ALL, Cancer immunology, Targeted therapy

Summary: Combining Immunotherapy and Chemotherapy in AML

Background:

• AML is a heterogeneous and aggressive blood cancer with poor survival, especially in elderly or relapsed/refractory patients (5-year survival < 30%).
• Conventional chemotherapy faces challenges including severe off-target toxicity and drug resistance.
• Immunotherapy offers more precise and potentially durable anti-leukemia effects but has limited efficacy when used alone.

Rationale for Combination Therapy:

• Chemotherapy can modulate the tumor microenvironment by:
  • Eliminating immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs)
  • Downregulating immune checkpoints such as PD-L1 on tumor cells
  • Inducing immunogenic cell death that enhances immune recognition
• These changes can synergize with immunotherapy to boost anti-leukemia immune responses and improve clinical outcomes.

Classes of Immunotherapy Combined with Chemotherapy:

1. Immune Checkpoint Inhibitors (ICIs):
   • Targets such as PD-1/PD-L1 and CTLA-4 to lift inhibitory brakes on T cells.
   • Example: Pembrolizumab combined with azacitidine (a hypomethylating agent) shows improved overall survival in relapsed/refractory AML.
2. Chimeric Antigen Receptor (CAR)–Engineered Cells:
   • CAR-T, CAR-NK, and CAR-macrophages are engineered to specifically recognize AML antigens to kill leukemia cells.
   • Activated T cells release cytokines (e.g., IFN-γ) to promote further immune activation.
3. Antibody-Drug Conjugates (ADCs):
   • Antibodies target AML cell surface antigens, internalize, then release cytotoxic payloads inside tumor cells.
   • Some cytotoxic drugs can diffuse to nearby cells, killing antigen-low or antigen-negative leukemic cells.
4. Bispecific Antibodies (BsAbs):
   • Recruit effector immune cells (e.g., T cells or NK cells) directly to tumor cells, enabling precise tumor killing.
   • Also stimulate cytokine release and proliferation of immune effectors.
5. Cancer Vaccines:
   • Present AML-associated antigens using dendritic cells (DCs) to activate T cells and induce cytotoxic T lymphocytes.

Challenges and Future Directions:

• Core challenges in combination therapy include:
  • Off-target toxicity to healthy cells
  • Tumor heterogeneity leading to varied antigen expression
  • Variable efficacy among patients
• Future efforts aim at precision medicine, tailoring treatment based on patient-specific tumor and immune profiles.

This combination approach leverages the strengths of chemotherapy to remodel the AML environment and enable immunotherapy to mount more effective and durable immune responses, with ongoing clinical trials trying to optimize regimens and overcome resistance.

If you want, I can also provide more detailed mechanisms, clinical trial data, or a diagrammatic explanation of the immune-oncology agents mentioned.

For years, the quest to eradicate cancer cells without causing harm to normal surrounding cells has been a fundamental aim of cancer therapies. Conventional methods often struggle to distinguish between cancerous and healthy cells, especially in diseases like AML where specific tumor antigens are difficult to identify. Despite significant advancements in allo-HCT, relapse remains a major challenge for many AML patients, underscoring the urgent need for innovative treatment methodologies.

In the study led by The University of Osaka, the research team embarked on an investigative journey to unearth tumor-specific antigens that could be targeted without affecting normal cells. They employed a systematic approach that had previously yielded success in multiple myeloma research where monoclonal antibodies were screened to identify those specifically reactive to cancer cells while sparing normal hematopoietic cells. By adapting this strategic methodology, the researchers aimed to pinpoint AML-specific antigens that could potentially serve as effective targets for CAR-based therapies.

The screening process began with the examination of thousands of monoclonal antibodies designed to bind to AML cells. Through a rigorous evaluation procedure, the team successfully narrowed the focus down to 32 distinct mAbs, each uniquely binding to AML cells. Among these, the antibody designated as KG2032 demonstrated a remarkable specificity by binding to AML cells in over half of the patient samples analyzed. Further investigation revealed that KG2032 binds preferentially to the HLA-DRB1 molecule, a promising discovery that highlights the therapeutic potential of targeting HLA-DRB1 in the context of AML.

In an intriguing twist of immunological specificity, the research showed that KG2032 is not just a general AML target but interacts with a specific subset of the HLA-DRB1 molecule. Specifically, this subset possesses an amino acid different from aspartic acid at the 86th position of the protein structure. This specificity implies that KG2032 can effectively target AML cells in individuals who possess this particular amino acid variant, while the corresponding donor from whom they receive stem cells through allo-HCT does not. This unique compatibility underscores the potential for developing a personalized therapeutic strategy tailored to individual patient profiles.

The implications of identifying HLA-DRB1 as a therapeutic target cannot be overstated, especially for patients who experience relapse post-allo-HCT. To validate their findings, the research team engineered KG2032 CAR T cells that lacked the reactive HLA-DRB1 allele and conducted both in vitro cell culture experiments and in vivo tests using mouse models. The results were striking; the CAR T cells exhibited potent and specific anti-AML activity, demonstrating significant efficacy without showing overt toxicity in the treated mice—a crucial consideration for clinical applicability.

In parallel to the achievements with CAR T cells, the researchers also explored the potential of cord blood-derived CAR NK cells, which were engineered in a similar fashion to produce encouraging outcomes. These findings collectively illustrate a novel therapeutic pathway that could significantly enhance treatment options available to AML patients, particularly in the context of relapse following allo-HCT. With the knowledge that both CAR T and NK cells have demonstrated efficacy in targeting HLA-DRB1-expressing AML cells, the research team is now poised to launch clinical trials to further evaluate the safety and effectiveness of these approaches in human patients.

Emerging from this study is a sense of optimism regarding the future of cancer treatments, particularly for individuals grappling with the challenges posed by relapsed AML. The innovative strategies developed in this research could transcend conventional treatment limitations, offering a tailored therapeutic intervention that effectively spares normal cells while targeting malignant ones. This paradigm shift in cancer therapy not only promises to improve patient outcomes but may also inspire further explorations into the intricacies of immunotherapy for various malignancies.

As the scientific community eagerly anticipates the outcomes of forthcoming clinical trials, the groundbreaking research from The University of Osaka stands as a testament to the power of interdisciplinary collaboration and innovative thinking in addressing the urgent challenges presented by aggressive cancers like AML. The journey from laboratory discoveries to clinical applications remains fraught with challenges, but the relentless pursuit of solutions in combating cancer continues to hold vast potential for transformative impact on patient care and survival.

In summary, the innovative CAR T and NK cell therapies targeting HLA-DRB1 present a beacon of hope for AML patients, particularly those who have faced relapse following allo-HCT. This pioneering research underscores the importance of specific targeting in cancer therapies and sets the stage for a new era in the treatment of hematological malignancies. As the research unfolds, the potential for personalized medicine becomes increasingly tangible, paving the way towards a future where effective and targeted therapies can improve survival rates and enrich the quality of life for patients afflicted with malignancies.

Subject of Research: Cells
Article Title: CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant
News Publication Date: 24-Mar-2025
Web References: N/A
References: N/A
Image Credits: The University of Osaka

Keywords: Health and medicine, AML, CAR T therapy, NK cells, HLA-DRB1, cancer treatment, immunotherapy, hematological malignancies.