Hematologic Cancers Break Down a ‘Checkpoint’: Targeting the PD-1/PD-L1 Axis

The anti-CD20 antibody rituximab, the first monoclonal antibody approved for treating cancer, revolutionized the therapy of B-cell lymphomas in 1997.[1] Recently, a new set of antibodies-this time targeting the immune regulatory “checkpoints” cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1)-have created a stir in the treatment of numerous solid tumors.[2,3] Thankfully, this approach has now moved into the hematologic cancer arena, adding another weapon to the growing arsenal of nonchemotherapy agents available to treat lymphomas, myeloma, and leukemias.

In the preceding review, Drs. Bryan and Gordon lay out the fast-evolving use of anti–PD-1/PD-L1 antibodies in the treatment of hematologic malignancies, now the focus of over 26 completed and ongoing clinical trials. While much of the recent enthusiasm has centered on the remarkable effects of PD-1 blockade in Hodgkin lymphoma,[4] early clinical trial results and preclinical studies in non-Hodgkin lymphomas and other blood cancers suggest that the impact will be much broader.

Just 10 years ago, excitement was building as our understanding increased regarding the role played by the PD-1/PD-L1 checkpoint in chronic infections and in thwarting antitumor immunity in preclinical animal models.[5] Numerous investigators thus sought to determine whether the PD-1 axis might be operative in common lymphoid cancers, and when this was in fact found to be the case, the stage was set for an explosion in fruitful research. Most prescient was the study of Yamamoto et al showing that in Hodgkin lymphoma, the malignant Reed-Sternberg cells expressed large amounts of PD-L1, and were surrounded by functionally impaired PD-1–positive T cells that could be reawakened by PD-1 antibody blockade.[6] Similar studies followed in T-cell lymphomas[7] and B-cell non-Hodgkin lymphomas.[8] Interestingly, the pattern of PD-L1 expression in B-cell lymphomas varied widely among histologic subtypes; expression was most prominent in the subset of diffuse large B-cell lymphomas with the “activated B cell” phenotype that carries a poorer prognosis. In follicular lymphoma, PD-L1 expression was largely absent from tumor cells but strongly expressed on macrophages permeating the interfollicular zones.[8] Myeloma cells were found to express generally lower levels of PD-L1.[9]

These and other studies prompted the clinical evaluation of PD-1 blockade in hematologic cancers. Given the high level of PD-L1 found at the surface of Reed-Sternberg cells,[6,10] perhaps the striking effectiveness of PD-1 blockade against Hodgkin lymphoma (87% for nivolumab, 53% for pembrolizumab) could have been anticipated.[4,11] Indeed, early clinical results with nivolumab have largely mirrored the preclinical PD-L1 findings, with B- and T-cell non-Hodgkin lymphomas having lesser rates of response, while no objective clinical responses have been seen in myeloma, whose tumor cells express the least amount of PD-L1.[12] However, only small numbers of blood cancer patients have been treated with anti–PD-1/PD-L1 agents to date; it will probably be several years before response rates to the various single agents are reliably determined.

In their review, Drs. Bryan and Gordon highlight the wide variety of agents already lined up for combination with PD-1 blockade in the clinic, including other checkpoint inhibitors (eg, anti–CTLA-4 agents), anti-CD20 antibodies, costimulatory antibodies such as those against anti–4-1BB, immunomodulatory drugs (IMiDs), kinase inhibitors, and tumor antigen vaccines. Critically, they also point out that because PD-1 blockade works by reawakening T cells to attack tumors, concurrent combination therapy with conventional cytotoxic chemotherapeutics might actually negate the beneficial effects, and the sequencing and timing of therapies may thus be crucial to achieving optimal efficacy. Moreover, it may make more sense to apply PD-1 blockade with other novel immunotherapies, such as chimeric antigen receptor (CAR) T cells.

While the results of the multitude of ongoing PD-1 blockade trials are eagerly awaited, it is clear that research involving the immunotherapy of blood cancers is moving swiftly through this first “checkpoint” at breakneck speed. It is sure to be a fascinating ride.

Financial Disclosure:Dr. Timmerman receives research funding from Bristol-Myers Squibb.

References:

1. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-33.

2. Ohaegbulam KC, Assal A, Lazar-Molnar E, et al. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21:24-33.

3. Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr Opin Immunol. 2015;33:23-35.

4. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-9.

5. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813-24.

6. Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111:3220-4.

7. Wilcox RA, Feldman AL, Wada DA, et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood. 2009;114:2149-58.

8. Andorsky DJ, Yamada RE, Said J, et al. Programmed death ligand 1 is expressed by non-Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17:4232-44.

9. Liu J, Hamrouni A, Wolowiec D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110:296-304.

10. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268-77.

11. Moskowitz CH, Ribrag V, Michot J-M, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). American Society of Hematology (ASH) Annual Meeting; Dec 6-9, 2014; San Francisco, Calif; abstr 290.

12. Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. ASH Annual Meeting; Dec 6-9, 2014; San Francisco, Calif; abstr 291.