A Combination of the Immunotherapeutic Drug Anti-Programmed Death 1 with Lenalidomide Enhances Specific T Cell Immune Responses against Acute Myeloid Leukemia Cells

Abstract

Immune checkpoint inhibitors can block inhibitory molecules on the surface of T cells, switching them from an exhausted to an active state. One of these inhibitory immune checkpoints, programmed cell death protein 1 (PD-1) is expressed on T cell subpopulations in acute myeloid leukemia (AML). PD-1 expression has been shown to increase with AML progression following allo-haematopoeitic stem cell transplantation, and therapy with hypomethylating agents. We have previously shown that anti-PD-1 can enhance the response of leukemia-associated antigen (LAA)-specific T cells against AML cells as well as leukemic stem and leukemic progenitor cells (LSC/LPCs) ex vivo. In concurrence, blocking of PD-1 with antibodies such as nivolumab has been shown to enhance response rates post-chemotherapy and stem cell transplant. The immune modulating drug lenalidomide has been shown to promote anti-tumour immunity including anti-inflammatory, anti-proliferative, pro-apoptotic and anti-angiogenicity. The effects of lenalidomide are distinct from chemotherapy, hypomethylating agents or kinase inhibitors, making lenalidomide an attractive agent for use in AML and in combination with existing active agents. To determine whether anti-PD-1 (nivolumab) and lenalidomide alone or in combination could enhance LAA-specific T cell immune responses, we used colony-forming immune and ELISpot assays. Combinations of immunotherapeutic approaches are believed to increase antigen-specific immune responses against leukemic cells including LPC/LSCs. In this study we used a combination of LAA-peptides with the immune checkpoint inhibitor anti-PD-1 and lenalidomide to enhance the killing of LSC/LPCs ex vivo. Our data offer a novel insight into how we could improve AML patient responses to treatment in future clinical studies.

Immunotherapeutic Potential of Mutated NPM1 for the Treatment of AML

“…Greiner et al showed that CD4 + and CD8 + T cells from AML patients could respond to peptides from the mutated regions of NPM1 [43]. They found that AML NPM1 mut patients with CTL responses against NPM1 mut peptide had better overall survival [45] and used LAAs as a specific method of stimulating T-cell immune responses against LSCs and determining which combinations of immunotherapeutics could further enhance AML cell killing [82].…”

“…Combinations of immunotherapeutic approaches are believed to increase antigenspecific immune responses against leukemic cells including LPC/LSCs. In this study, we used a combination of LAA-peptides with the ICI, αPD-1 (nivolumab), and lenalidomide to enhance the killing of LSC/LPCs ex vivo [82]. We used primary cells from AML patients and observed the T-cell responses of all patients in vitro.…”

“…enhance anti-leukemic responses. We have shown that these combinations can increase antigenspecific immune responses against leukemic cells as well as LPC/LSC [82,83]. Image generated using information from the following articles [5][6][7][8]27,39,41,47,55,56,[64][65][66][67][68][69][70][71]80,[83][84][85][86][87][88].…”

A Direct Comparison, and Prioritisation, of the Immunotherapeutic Targets Expressed by Adult and Paediatric Acute Myeloid Leukaemia Cells: A Systematic Review and Meta-Analysis

“…With the advent of next generation immunotherapeutic strategies including Boolean gating, reversing T cell exhaustion, and split/SUPRA CARs (recently reviewed in [115]), we see an opportunity to address the current challenges limiting the safety and efficacy of CAR-T cells for cancer treatment. It is likely that a combinational approach can provide a safe delivery method for immunotherapeutic targeting of AML, and, indeed, recent studies suggest the combination of an immune checkpoint inhibitor and antigen targeting, as well as immune modulation, could further enhance anti-leukaemic responses [116,117].…”

The Association between Immune Checkpoint Proteins and Therapy Outcomes in Acute Myeloid Leukaemia Patients

“…The most recent in vitro study on leukemic cells and lenalidomide in combination with nivolumab (anti-PD-1), suggested that certain populations of cells might benefit more from ICI use. That combination was shown to be highly effective in supporting a population of leukemic antigen-specific cytotoxic T cells, especially toward blasts of the NPM mut AML group [ 11 ]. In contrast, blockage of PD-L1 on leukemic cells was associated with cell cycle arrest, inhibition of proliferation and activation of apoptotic pathways.…”