Immunotherapy Poised to Transform Cancer Treatment

Clifford A. Hudis, MD

Immunotherapy has become an increasingly appealing therapeutic strategy for patients with cancer, with many late-stage clinical trials demonstrating overall survival (OS) advantages in melanoma and castration-resistant prostate cancer.

More recently, non-small cell lung cancer (NSCLC) has become a focus for the next generation of immune-based therapeutic strategies. Immunotherapy, in particular the use of monoclonal antibodies that block inhibitory immune checkpoint molecules and therefore enhance the immune response to tumors, also has shown clinical promise in advanced solid tumors.

Research findings from clinical trials testing immunotherapies have been highlighted at major oncology conferences throughout 2013, including this year’s meeting of the American Society of Clinical Oncology (ASCO), where the most promising results came from an emerging class of antibodies that target the programmed death-1 (PD-1) pathway to take the brakes off the patient’s immune system, employing the same type of “checkpoint blockade” approach that the monoclonal antibody ipilimumab (Yervoy) pioneered in metastatic melanoma and which received FDA approval in 2011.

Immunotherapy: The Basics

Immunotherapy refers to a diverse range of therapeutic approaches that aim to harness the immune system to reestablish a targeted antitumor immune response. The goal of cancer immunotherapy is to enable the patient’s immune system to specifically recognize and kill cancer cells.^3-7

There are two distinct types of immunotherapy: Passive immunotherapy uses components of the immune system to direct targeted cytotoxic activity against cancer cells, without necessarily initiating an immune response in the patient, whereas active immunotherapy actively triggers an endogenous immune response. Passive strategies include the use of the monoclonal antibodies (mAbs) produced by B cells in response to a specific antigen.⁴ The development of hybridoma technology in the 1970s and the identification of tumor-specific antigens permitted the pharmaceutical development of mAbs that could specifically target tumor cells for destruction by the immune system.

Thus far, mAbs have been the biggest success story for immunotherapy; the top three best-selling anticancer drugs in 2012 were mAbs.⁸ Among them is rituximab (Rituxan), which binds to the CD20 protein that is highly expressed on the surface of B cell malignancies such as non-Hodgkin’s lymphoma (NHL). Rituximab is approved by the FDA for the treatment of NHL and chronic lymphocytic leukemia (CLL) in combination with chemotherapy. ⁹ Another important mAb is trastuzumab (Herceptin), which revolutionized the treatment of HER2-positive breast cancer by targeting the expression of HER2.¹⁰

In order to actively drive an antitumor immune response, therapeutic cancer vaccines have been developed. Unlike the prophylactic vaccines that are used preventatively to treat infectious diseases, therapeutic vaccines are designed to treat established cancer by stimulating an immune response against a specific tumor-associated antigen.

The advantage of active immunotherapies is that they have the potential to provide long-lasting anticancer activity by engaging both the innate and adaptive arms of the immune response. While mAbs are typically considered passive immunotherapies, there is increasing evidence that they also induce an adaptive immune response via a “vaccination-like” effect.¹¹

In 2010, sipuleucel-T (Provenge) was approved by the FDA for the treatment of metastatic, castration-resistant prostate cancer based on the results of the IMPACT (Immunotherapy Prostate Adenocarcinoma Treatment) trial in which it improved OS by 4.1 months and reduced the risk of death by 22% versus placebo.^1,2 Despite these successes, immunotherapy has previously faced skepticism and significant disappointment; however, it is now beginning to gather momentum, particularly since the discovery of the immune checkpoints and the success of their therapeutic targeting.

The Cancer Research Institute, a New York City nonprofit that provides funding to scientists in the field, notes on its website that more than 1050 cancer immunotherapy clinical trials are now enrolling patients across a range of tumor types, many of which are phase III trials. (

http://www.cancerresearch.org/

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In an OncLiveTV interview during the 2013 ASCO Annual Meeting, Clifford A. Hudis, MD, ASCO president, chief of the Breast Cancer Medicine Service, and attending physician, Memorial Sloan-Kettering Cancer Center in New York City, discussed his optimism surrounding immunotherapy for cancer care.

“What we now have is evidence that combinations of drugs can be effective,” with never-seenbefore results in metastatic melanoma.

“I’m optimistic about this for two reasons,” he continued. “The first is the narrow application in melanoma, a very difficult to treat disease, historically. Second, these results may well predict a future where we can manipulate the immune system productively to treat a variety of metastatic solid tumors. I’m very optimistic that we will see rapid expansion of this kind of immunology research across tumor types.”

What does this mean for the oncology nurse practicing today? Over the course of the next month, Oncology Nursing News will present some of the latest cancer immunotherapy research, with a focus on new clinical findings in the development of PD-1/PDL1— targeting agents. We will also feature opinions from oncology nursing professionals on how these therapies are reshaping clinical practice as they work to educate patients and help them to proactively and safely manage any immune-related adverse events.

References

• Bilusic M, Madan RA. Therapeutic cancer vaccines: the latest advancement in targeted therapy. Am J There. 2012;19(6):e172.
• Kantoff PW, Higano CS, Shore ND. Sipuleucel-T immunotherapy for castration resistant prostate cancer. New Engl J Med. 2010;363(5):411.
• Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy-inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580.
• Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480.
• Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116:1757.
• Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate antitumor immunity. Curr Opin Immunol. 2012;24:207.
• Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237.
• FiercePharma. Top 10 best-selling cancer drugs. http://www.fiercepharma. com/special-reports/top-10-best-selling-cancer-drugs/top-10-bestselling- cancer-drugs. Accessed October 30, 2013.
• Czuczman MS, Grillo-Lopez AJ, White CA. Treatment of patients with lowgrade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17(1):268.
• Slamon D, Leyland-Jones B, Shak S. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Engl J Med. 2001;344:782.1
• Beck A, Wurch T, Bailly C. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010;10(5):345.