April 2014, Part 1

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The New Generation of Immunotherapies A Focus on the PD-1 Pathway

Matthew Welding, MPH


It is becoming increasingly evident that cancer is a highly heterogeneous disorder. Researchers have begun to recognize that cancer progression is affected not just by genetic mutations, but by the interaction between tumors and the microenvironment in which they thrive. The evolution in understanding tumor biology and genetics has helped to usher in a new era of personalized medicine in which patients receive treatments tailored to the genetic makeup and biology of their tumors.1,2

A Changing Paradigm

In the past, tumors were viewed as undifferentiated masses of proliferative cells. However, as the understanding of tumor biology has evolved, it has become apparent that tumors are complex bodies composed of heterogeneous, organized groups of cells with specific functions collectively contributing to tumor growth and progression.3 There is an increasing recognition that tumors interact with their microenvironment, which includes a complex relationship with the body’s immune system. The body’s immune response is not always successful in eliminating cancer cells, and a key reason is that tumors can create an immunosuppressive environment.4

When normal cells turn into cancer cells, they display altered surface proteins. Although the body’s immune system provides continuous surveillance, detecting and eradicating cells that have undergone malignant transformation, some new cancer cells have modifications that facilitate evasion of host defense mechanisms.

Some tumor cells downregulate their cell surface major histocompatibility complex (MHC), which is required for recognition by tumor antigen-specific T lymphocytes. As a result, these tumor cells become less recognizable by the immune system and more resistant to immune-mediated destruction. Similarly, cancer cells can overexpress cytokines normally involved in tissue repair, remodeling, and homeostasis, “tricking” the immune system, and thereby promoting angiogenesis and tumor growth. The effects of these immunosuppressive cytokines can be localized and/or systemic and may contribute to metastasis.5

The PD-1 Pathway and Pembrolizumab

Researchers are focusing their efforts on the most therapeutically accessible checkpoints, which include inhibitory receptors on the outer membrane of T lymphocytes and their corresponding ligands on tumor cells, as these molecules can be blocked specifically with antibodies.6 The 2 checkpoint receptors that have been most actively studied in the context of clinical cancer immunotherapy are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1).7

CTLA-4, the first immune checkpoint receptor to be clinically targeted, is a member of the Ig superfamily and is expressed on the surface of T-helper cells. The PD-1 pathway has also emerged as a fertile area of cancer research, and recent evidence has confirmed the pivotal role of the PD-1 receptor and its ligands PD-L1 and PD-L2 in maintaining an immunosuppressive tumor microenvironment.7

Research has demonstrated that expression of the PD-L1 and PD-L2 ligands on cancer cells allows a tumor to utilize the PD-1 pathway to protect itself from an immune response. As a result, cancer cells are able to exploit the PD-1 checkpoint pathway and continue to thrive and proliferate.6 Data suggest that adaptive resistance continues to take place in advanced tumors, although the immune system continues to conduct surveillance. In such cases, tumors are able to continue evading immune destruction by upregulating ligands for immune receptors on tumor-specific lymphocytes within the microenvironment in which the tumor thrives.

The article “Review: The Role of the PD-1 Pathway in Immunotherapy” focuses on the role of the PD-1 pathway in metastatic cancer (see pages 15-17 and 22). In particular, it reviews the immune checkpoint blockade, the role of the PD-1 checkpoint pathway in modulating the immune system, as well as evidence of clinical activity in investigational PD-1 blockers.

Omid Hamid, MD, and colleagues focus their article on the emerging therapy pembrolizumab (see “Checkpoint Inhibition of PD-1: The Promise of Pembrolizu­mab (MK-3475) and Beyond,” pages 8-14), including published clinical data, its use in non–small cell lung cancer, toxicity, as well as biomarkers and upcoming studies.

In his article, Daniel C. Cho, MD, explores the sequencing of therapies for patients with renal cell carcinoma (see “Sequential Therapy for Renal Cell Carcinoma,” pages 19–22). He emphasizes that sequential therapy is a reality for patients with renal cell carcinoma and must be individualized based on clinical factors. Treatment sequences that begin with immunotherapy or molecularly targeted agents are discussed, as are novel therapeutic agents and novel technologies used in the treatment of renal cell carcinoma.

As the understanding of PD-1 pathway biology and its critical role in immunosuppression has evolved, there has been a groundswell fueling the clinical development of PD-1 pathway blockers. Numerous trials are under way to evaluate the potential of anti–PD-1 immunotherapy.8 In addition, tumor cell expression of PD-L1 has emerged as a potential biomarker of response, consistent with pathway biology.7 Anti–PD-1 therapies are also being investigated in current or anticipated clinical trials.9

The immune checkpoint blockade is a promising emerging approach to immunotherapy, and clinical findings thus far indicate that the PD-1 checkpoint pathway represents a significant opportunity to enhance antitumor immunity with the potential to produce durable responses. Results from planned and ongoing clinical trials in a variety of tumor types may further clarify the role of the PD-1 pathway in cancer therapies.


  1. Roth BJ, Krilov L, Adams S, et al. Clinical cancer advances 2012: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2013;31:131-161. Erratum in: J Clin Oncol. 2013;31:2063.
  2. Marte B. Tumour heterogeneity. Nature. 2013;501:327.
  3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
  4. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(suppl 8):viii6–viii9.
  5. Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111:3635-3643.
  6. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209:201-209.
  7. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.
  8. Merck & Co. MK-3475; enrolling locations in the United States. Search results. www.merck.com/clinical-trials/search.html?kw=MK-3475&ctry=United%20States. Accessed April 3, 2014.
  9. Genentech. Pipeline. www.gene.com/medical-professionals/pipeline. Accessed April 3, 2014.
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