Venkata Lokesh BattulaPhD
The University of Texas MD Anderson Cancer Center
Project Term: July 1, 2023 - June 1, 2026
In order to develop a novel immunotherapy approach to treating AML, we propose targeting B7-H3 (CD276), a promising immune checkpoint that has been reported to inhibit NK cell activation. We have generated a novel anti–B7-H3 monoclonal antibody (T-1A5) to block B7-H3 function, showing the best in vitro and in vivo activity against AML cells. We will test the hypothesis that combination strategies such as targeting B7-H3 along with BCL2 inhibition (venetoclax) or IL-15r agonist (NKTR-255) result in synergistic inhibition of AML growth.
AML is the most common acute leukemia in adults. 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. Here, we propose to target B7-H3 (CD276), a promising pan-cancer antigen as well as an immune checkpoint that has been reported to inhibit 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 outcomes. 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 also suggests that a combination of B7-H3 blocking antibody, T-1A5 and the FDA-approved BCL-2 inhibitor, venetoclax, synergistically induced NK cell-induced apoptosis in AML cells. Our preliminary data suggest that a combination of B7-H3 inhibition with a novel compound (NKTR-255) which was developed based on a cytokine IL-15 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, first, we will test fully humanized version of the T-1A5 antibody (huT-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 huT-1A5 and venetoclax against drug-resistant, recurring AML models in mice. We will also investigate the mechanism of enhanced NK cell response to huT-1A5 and venetoclax combination therapy. Finally, we will test the hypothesis that targeting B7-H3 using huT-1A5 antibody eliminates AML stem cells but spares normal stem cells. Moreover, the effect of huT-1A5 on leukemia stem cells will be tested in vivo using mouse models. Since some of the drugs used in this study are already used in the frontline therapy for treating AML, such as venetoclax, the combination approaches such as B7-H3 inhibition could be quickly translated to the clinic.