Targeting Immune-Checkpoint Protein B7-H3 in Acute Myeloid Leukemia
Abstract
The study addresses one of the FY22 Rare Cancer Research Program Focus Areas, Therapy. Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age of 68 years at presentation. Several mechanisms contribute to AML aggressiveness, among which is the ability of AML cells to evade the anti-tumor immune response. Numerous efforts have been directed at identifying the molecules and signaling pathways that contribute to AML immune evasion. While several clinical trials have evaluated the inhibition of immune checkpoint proteins PD-1/L1 and CTLA4 in AML patients, this approach has not resulted in any meaningful benefit. The majority of patients with relapsed AML are inherently resistant to PD1/L1 or CTLA4 inhibitors. Consequently, there is a pressing need to identify additional immune checkpoints that contribute to AML immune evasion. In order to develop a new immunotherapy approach to treating AML, we propose to target B7-H3 (CD276), a promising pan-cancer antigen as well as an immune checkpoint that has been reported to inhibit natural killer (NK)/T cell activation. B7-H3 protein is overexpressed in several solid tumors and hematologic malignancies but is undetectable in normal tissues. We have recently reported that B7-H3 is overexpressed in a major proportion of adult AML blasts and that its expression is associated with poor survival outcome. Moreover, inhibition of B7-H3 expression enhances NK cell-mediated apoptosis in AML cells. We have generated a novel anti-B7-H3 monoclonal antibody (mAb) to block B7-H3 function and enhance NK cell-induced apoptosis in AML cells. The clone T-1A5 has shown the best in vitro and in vivo activity against AML cells. Recent data also suggest that inhibition of BCL2 in AML cells enhances NK cell-induced apoptosis in AML cells. Our preliminary data suggests that a combination of B7-H3 blocking antibody, T-1A5, and the U.S. Food and Drug Administration (FDA)-approved BCL-2 inhibitor, venetoclax, synergistically induced NK cell-induced apoptosis in AML cells. We have reported that B7-H3 expression is positively correlated with CD34 in AML cells. Our preliminary data using a large set of AML patient samples (n=800) suggest that B7-H3 protein expression is also positively correlated with other known stem cell genes including SOX2, AXL, and NOTCH1. Moreover, our data suggests that a combination of B7-H3 inhibition with a novel IL-15 agonist (NKTR-255) and BCL2 inhibition by venetoclax synergistically induce NK cell-induced killing in AML cells. Based on this evidence, we hypothesize that B7-H3 is an immune checkpoint protein and a therapeutic target in AML; targeting B7-H3 in combination with NK cell activity enhancers is synergistic in eliminating AML stem cells and inhibiting AML growth. In our approach, we will first test the partially humanized (chimeric) version of the T-1A5 antibody (chT-1A5) and NKTR-255 combination against primary AML cells with variable B7-H3 expression as well as test the combination in vivo using B7-H3 AML in mouse models. Next, to determine the effect of BCL2 inhibition on NK cell response to B7-H3 targeted therapy in AML, we will test the therapeutic efficacy of the combination of chT-1A5 and venetoclax against drug-resistant, recurring AML models in mice. We will also investigate the mechanism of enhanced NK cell response to chT-1A5 and venetoclax combination therapy. Finally, we will investigate the effect of targeting B7-H3 on the elimination of AML stem cells. We will test the hypothesis that targeting B7-H3 using chT-1A5 antibody eliminates AML stem cells but spares normal stem cells using primary peripheral blood and bone marrow samples from healthy donors and patients with AML. Moreover, the effect of chT-1A5 on leukemia stem cells will be tested in vivo using mouse models. These experiments will establish B7-H3 as a biomarker and therapeutic target in AML. Moreover, these studies will develop nove
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311026
Entities
People
- Venkata Lokesh Battula
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army