Dissecting the mechanistic basis of response to combined decitabine and ipilimumab following hematopoietic stem cell transplantation for relapsed acute myelogenous leukemia

• Applicant: Dr. Livius Penter
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 430138413

Allogeneic hematopoietic stem cell transplantation (HCT) provides potentially curative therapy for high-risk acute myelogenous leukemia (AML), mainly based on potent graft-versus-leukemia effects (GvL). Relapse of AML after HCT remains the key source of mortality, and hence efforts to enhance GvL are of high priority. At the same time, despite the long-established clinical track record of HCT, the mechanistic basis of GvL remains not fully elucidated.The recent clinical availability of immunomodulatory agents such as checkpoint blockade along with existing active therapeutics, for example hypomethylating agents, opens new doors for enhancing GvL. Clinical trials with single use of these agents have demonstrated promising clinical activity in addressing post-HCT AML relapse, suggesting combination of these treatment modalities could provide even greater effectiveness. This was the rationale for an ongoing NCI ETCTN/CTEP phase I study (#10026) at DFCI which seeks to probe the combination of ipilimumab and decitabine in AML relapse post-HCT. Early data indicate that this approach is clinically active.We hypothesize that responders to combined decitabine and ipilimumab will have distinct disease and immune microenvironment properties and show activated T cell responses against tumor antigens. The dedicated longitudinal biospecimen collection from this study provides a rich opportunity to dissect the basis of response following this novel therapeutic combination. Today powerful research tools are available to study cancer immunology at unprecedented depth. Massively parallel sequencing, high throughput single cell technologies and computationally guided antigen discovery approaches provide exciting foundations for comprehensive evaluation of samples from study subjects. Through application of advanced immunogenomic tools and building on my experience in single T cell receptor (TCR) analysis of tumor-reactive T cells, my objective is to elucidate the immune mechanisms underlying GvL effects.Aim 1 will thus undertake genomic evaluation of tumor samples to link response to disease-specific properties such as tumor antigen load and expression of genes critical to immune signaling pathways. Aim 2 will track quantitative and qualitative changes in the immune microenvironment using flow cytometry, single-cell RNA sequencing and mass cytometry. Aim 3 will exploit single TCR sequencing and methods to uncover cognate antigens of tumor-reactive TCRs to understand tumor antigen-T cell interactions driving responses.Completion of these aims is expected to reveal important principles of immune responses after HCT and will shed light on how checkpoint blockade and hypomethylating agents enhance GvL. This will have direct clinical implications as the results could aid in identifying patients that benefit from this therapeutic combination and might pave the way for developing novel therapeutic approaches like vaccination or adoptive T cell transfer strategies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Catherine J. Wu