BM NICHE DISRUPTION AND IMMUNOTHERAPY IN HEMATOLOGICAL MALIGNANCIES

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The DiPersio Unit strives to optimize immunotherapy, including allogeneic hematopoietic stem cell transplantation (alloHSCT), for treating hematological malignancies. HSCT is the only curative therapy for many hematological malignancies and some non-malignant diseases such as hemoglobinopathies, autoimmune diseases, and inherited disorders of metabolism. Key obstacles to the success of HSCT include collecting sufficient numbers of hematopoietic stem/progenitor cells (HSPCs) to proceed to transplant, control of graft- versus-host disease (GvHD), and treating disease recurrence both before and especially after HSCT. Dr. DiPersio has focused over the last 25 years on overcoming these obstacles to HSCT through a bench-to-bedside and back again research approach. I have been fortunate to spend my entire 20-year post-graduate research career working with Dr. DiPersio. During this time, I contributed to 37 of Dr. DiPersio’s peer-reviewed manuscripts, performed pre-clinical studies for five projects that led to first-in-human clinical trials, completed correlative studies for 21 different clinical trials involving over 550 patients, and assisted in the training of 12 post-docs/fellows and nine technicians. Dr. DiPersio’s research program over the next several years will use our strengths in preclinical modeling, cancer genomics and the design and execution of early phase clinical trials to (1) develop novel methods for HSPC mobilization and GvHD treatment; (2) define the genetic and epigenetic changes that contribute to AML relapse after alloHSCT; and (3) perform clinical trials testing bispecific antibody or chimeric antigen receptor T cell (CART) therapies to treat hematological malignancies before or after HSCT. Successful HSCT requires the infusion of an adequate number of HSPCs that are capable of homing to the bone marrow and regenerating hematopoiesis in a timely fashion. We have developed novel polyethylene glycol (PEG)-conjugated small molecule inhibitors of the integrin very late antigen 4 (VLA-4) and demonstrated that they synergistically mobilize HSPCs in mice and non-human primates when combined with plerixafor, a CXCR4 inhibitor. In research program 1, I am testing the efficacy of long-acting versions of our PEGylated VLA-4 inhibitors to (1) mobilize murine HSPCs when combined with BL-8040, a long-acting CXCR4 inhibitor and (2) treat GvHD after alloHSCT when given alone or in combination with baricitinib, a JAK1/JAK2 inhibitor. In research program 2, I am defining minor histocompatibility antigens (mHAs) in mice and man and examining if relapse after alloHSCT is mediated in part via downregulation or loss of immunogenic mHAs. Since 30%-50% of post- alloHSCT AML relapses exhibit MHC Class II downregulation, I am examining the mechanisms of MHCII downregulation in AML and developing approaches to re-induce MHCII on these immunologically cloaked tumors. In research program 3, I am completing correlative studies for trials evaluating the efficacy of Flotetuzumab, a CD123´CD3 bispecific antibody, in patients with AML who relapse after chemotherapy or alloHSCT and testing if CART therapy can be enhanced via administration of long-acting human IL-7 (NT-I7).