Anti-Icos Monoclonal antibody, clone 8F.28H0 [PE]

Acute myeloid leukemia (AML) is generally considered a poorly immunogenic malignancy, displaying a "non-inflamed" leukemia microenvironment (LME), leading to T cell tolerance. However, the immune landscape of AML is much more heterogeneous. Since B7 expression is regarded as a consequence of an interferon-mediated "inflammatory" phenotype, we have investigated by flow cytometry the B7 checkpoint ligands B7.1, B7.2, programmed death ligand 1 (PD-L1), PD-L2, ICOS-L, B7-H3, and B7-H4 on the AML blasts of 30 newly diagnosed patients and their corresponding receptors [cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and inducible T cell costimulator (ICOS)] on bone marrow (BM) T cell maturation populations. We could thus evidence B7-negative and B7-positive leukemias either with an isolated expression or part of eight different checkpoint ligand "signatures" that always included an inhibitory B7 molecule. B7-positive AMLs encompassed intermediate and adverse European Leukemia Net (ELN) risk cases and displayed mainly central memory CD4+ T cells with high ICOS levels and effector CD8+ T cells with high PD-1 expression. B7-negative cases were rather classified as AML with recurrent genetic anomalies and displayed predominantly naive T cells, with the exception of NPM1 mutated AMLs, which expressed B7-H3. These different B7 immune profiles suggest that specific immunotherapies are required to target the distinct immune evasion strategies of this genetically heterogeneous disease.

Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.