Targeting Immune Checkpoints in Hematologic Malignancies

Abstract

The use of antibodies that target immune checkpoint molecules on the surface of T-lymphocytes and/or tumor cells has revolutionized our approach to cancer therapy. Cytotoxic-T-lymphocyte antigen (CTLA-4) and programmed cell death protein 1 (PD-1) are the two most commonly targeted immune checkpoint molecules. Although the role of antibodies that target CTLA-4 and PD-1 has been established in solid tumor malignancies and Food and Drug Administration approved for melanoma and non-small cell lung cancer, there remains a desperate need to incorporate immune checkpoint inhibition in hematologic malignancies. Unlike solid tumors, a number of considerations must be addressed to appropriately employ immune checkpoint inhibition in hematologic malignancies. For example, hematologic malignancies frequently obliterate the bone marrow and lymph nodes, which are critical immune organs that must be restored for appropriate response to immune checkpoint inhibition. On the other hand, hematologic malignancies are the quintessential immune responsive tumor type, as proven by the success of allogeneic stem cell transplantation (allo-SCT) in hematologic malignancies. Also, sharing an immune cell lineage, malignant hematologic cells often express immune checkpoint molecules that are absent in solid tumor cells, thereby offering direct targets for immune checkpoint inhibition. A number of clinical trials have demonstrated the potential for immune checkpoint inhibition in hematologic malignancies before and after allo-SCT. The ongoing clinical studies and complimentary immune correlatives are providing a growing body of knowledge regarding the role of immune checkpoint inhibition in hematologic malignancies, which will likely become part of the standard of care for hematologic malignancies.

Fig. 1.

Malignant hematologic cells express ligand for CTLA-4 and PD-1 and are therefore direct targets for immune checkpoint blockade. (A) Malignant solid tumor cells express PD-L1 and PD-L2 and can attenuate the antitumor immune response through direct interactions with PD-1 on the tumor specific T cells. Immune checkpoint blockade in solid tumor malignancies that interferes with the PD-1/PD-L1 pathway directly removes this inhibition. (B) Anti-CTLA-4 is effective in solid tumor malignancies through its influence on antigen presenting cells (APC) during immune priming. (C) Malignant hematologic cells express PD-L1 and PD-L2, but also express CTLA-4. Because malignant hematologic cells can act as APC, the use of anti-CTLA-4 antibodies in this setting therefore can directly modulate the immune response against the malignant hematologic cell.

Fig. 2.

The timing of the administration of immune checkpoint blockade is critical in determining treatment success in hematologic malignancies. The immune system is often attenuated in patients with active leukemia because of the accumulation of malignant cells in the bone marrow microenvironment. Before, or concomitant with, the administration of immune checkpoint inhibition, the underlying leukemia must be reduced to allow for some degree of immune reconstitution. One such approach includes the administration of immune checkpoint inhibitors to leukemia patients in remission or with a low leukemia burden. At this point, immune checkpoint inhibition can be administered (A) as an adjunct to cellular therapy, including stem cell transplantation, (B) in conjunction with vaccines, or (C) as a single agent.