Elsevier

Seminars in Oncology

Volume 42, Issue 4, August 2015, Pages 587-600
Seminars in Oncology

Antagonists of PD-1 and PD-L1 in Cancer Treatment

https://doi.org/10.1053/j.seminoncol.2015.05.013Get rights and content

The PD-1 pathway, comprising the immune cell co-receptor Programmed Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates local immunosuppression in the tumor microenvironment. Drugs designed to block PD-1 or PD-L1 “release the brakes” on anti-tumor immunity and have demonstrated clinical activity in several types of advanced cancers, validating this pathway as a target for cancer therapy. Two such drugs have recently been approved to treat melanoma and lung cancers, and regulatory approvals in first- and second-line settings for additional cancer types are anticipated. The manageable safety profile of PD-1/PD-L1 blocking drugs identifies them as suitable for outpatient administration and the development of combinatorial therapies. Ongoing studies aim to identify biomarkers to guide patient selection, which would further improve the risk:benefit ratio for these drugs.

Section snippets

Melanoma

The annual incidence of melanoma continues to rise worldwide, and despite recent regulatory approvals for ipilimumab and several kinase inhibitors, more effective treatment options for patients with advanced disease are needed. Clinical experience with agents blocking PD-1 and its ligands in melanoma began in 2006 with the first-in-human trial of nivolumab (Opdivo, BMS-936558, MDX-1106, ONO-4538; Bristol-Myers Squibb, Princeton, NJ) involving 39 patients with various advanced,

Non-Small Cell Lung Cancer

Unlike melanoma, historically, lung cancer has not been considered to be an immunogenic tumor. Signals of activity seen in early-phase studies of agents targeting PD-1 and PD-L1 have been both surprising and exciting, with the potential for durable disease control for the first time in patients with advanced NSCLC. NSCLC is responsible for almost one third of cancer-related deaths in the United States and is the leading cause of cancer mortality for both men and women worldwide.21 Despite

Renal Cell Carcinoma

Approximately 64,000 new cases and 14,000 deaths from kidney cancer are expected each year in the United States. The main systemic treatment options for patients with advanced kidney cancer, in particular clear cell RCC (ccRCC), include inhibitors of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways. While these drugs have had a significant impact on ccRCC management, durable disease control is rare.30 Only high-dose interleukin-2 induces durable

Gynecologic Cancers

Ovarian cancer has long been recognized as an immunogenic tumor. TIL-rich and TIL-poor ovarian cancers have 5-year survival rates of 38% and 4.5%, respectively.40 High PD-L1 expression by ovarian cancer cells is inversely associated with numbers of intraepithelial CD8+ TILs and is associated with a poor prognosis.41 Nivolumab was tested in 15 patients with relapsed platinum-resistant ovarian cancer, with a 23% ORR and a 54% DCR (CR+PR+stable disease).42 A phase I study of BMS-936559 anti–PD-L1

Squamous Head and Neck Cancer

Squamous cell carcinoma of the head and neck (SCCHN) is the fifth commonest cancer worldwide, and median survival for patients with advanced disease is approximately 13 months.21 Both human papilloma virus (HPV)-associated and non–HPV-associated head and neck tumors have prominent lymphoid infiltrates, and there is evidence in HPV-associated tumors for adaptive immune resistance, with dysfunctional TILs which express PD-1 and tumor cells with high levels of PD-L1 expression.52

Anti-tumor

Biomarkers

PD-1/PD-L1 checkpoint blockade has demonstrated durable objective tumor regressions and prolonged disease stabilization in significant proportions of patients with multiple cancer types, and has also been associated with “unconventional” activity profiles such as delayed responses, apparent disease progression before regression, and the possibility of a second response following re-induction therapy for disease progression. Although the PD-1 pathway blockers tested to date have been generally

Conclusions

Early evidence of significant and durable clinical activity of PD-1 pathway blocking drugs across a wide spectrum of cancer types has ushered in a new age of cancer immunotherapy and has firmly established this treatment modality in the oncologic armamentarium. Following recent regulatory approvals for pembrolizumab and nivolumab for patients with treatment refractory advanced melanoma, approvals for additional cancer types are anticipated. The generally manageable safety profile of

Acknowledgment

The authors would like to thank Joel C. Sunshine for helpful discussions.

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  • Cited by (0)

    Supported in part by the National Institutes of Health R01 CA142779 (J.M.T., S.L.T.); the Melanoma Research Alliance, the Barney Foundation, the Laverna Hahn Charitable Trust, and Moving for Melanoma of Delaware (E.J.L., J.M.T., S.L.T.); Stand Up 2 Cancer-Cancer Research Institute grant SU2C-AACR-DT1012 (E.J.L., P.M.F., J.M.T., S.L.T.); Bristol-Myers Squibb (J.M.T., S.L.T.); Roche (L.A.E.); the Breast Cancer Research Foundation (L.A.E.); and a LUNGevity Career Development Award (P.M.F.).

    Financial disclosures/conflicts of interest: E.J.L. receives research support from AstraZeneca and Genentech and is a consultant for Amgen. P.M.F. is a consultant (uncompensated) for Celgene, Boehringer-Ingelheim and Myriad. H.-J.H. receives research support from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, SFJ Pharmaceuticals Group and Genentech, and has received honoraria from Bristol-Myers Squibb and Aveo Pharmaceuticals. L.A.E. receives research funding from Genentech and Roche, and is a consultant for Bristol-Myers Squibb, Celgene, Vaccinex, and Aveo Pharmaceuticals. J.M.T. receives research support from Bristol-Myers Squibb and is a member of advisory boards for Bristol-Myers Squibb. S.L.T. receives research support from Bristol-Myers Squibb and is a consultant for Five Prime Therapeutics, GlaxoSmithKline, and Jounce Therapeutics; her spouse is a consultant for MedImmune Inc and Potenza Therapeutics, holds stock options in Jounce and Potenza, and receives royalties from Bristol-Myers Squibb, MedImmune and Potenza through his institution.

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