Immuno-oncology (I-O) is set to revolutionize the field of cancer care. Harnessing the immune system to attack cancer cells was ideated after scientists discovered the viral origins of some forms of cancer. Cancer vaccines were subsequently developed as prophylactic treatment and as therapy. Currently, 3 prophylactic vaccines approved for use by the FDA against the human papilloma virus (HPV)—responsible for most cases of cervical cancer—are available in the United States: Gardasil (HPV 6, 11, 16, 18), Gardasil 9 (HPV 9), and Cervarix (HPV 16 and 18).1 Gardasil is a Merck product and Cervarix was developed by GlaxoSmithKline Biologicals. On the therapeutic front, several companies continue their research efforts, but the lone FDA-approved product is Provenge (sipuleucel-T)2 from Dendreon Corporation, indicated for the treatment of asymptomatic or minimally symptomatic, metastatic, hormone- refractory prostate cancer.3 However, the drug’s front-end cost ($93,000) coupled with its complex personalization protocol resulted in a slump in sales, and Dendreon finally filed for bankruptcy late last year.4 While CEO W. Thomas Amick has assured that Provenge will remain commercially available to patients and providers during the process, there are reports that Valeant Pharmaceuticals International, Inc would buy the immunotherapy from Dendreon (see page SP76). Several other cancer vaccines, both prophylactic and therapeutic, are currently under development. Additionally, several clinical trials are ongoing with approved and novel vaccines.().
An early approach that was tried, but failed, was treating patients with cytokines and interferons. The primary reasons for failure included lack of specificity, limited efficacy, and toxicity.5 Present-day advances in I-O can be attributed to a paradigm shift in understanding the disease: in the late 1990s and early 2000s, cancer was considered a disease of genetic origins, with specific “hallmarks,” including sustained proliferation, resistance to apoptosis, the ability to promote angiogenesis, and the ability to promote invasion and metastasis.6 This view disregarded the dynamic nature of the interaction of the tumor with its microenvironment, which included the “normal” cells in the surrounding tissue as well as the immune system.7 Discovery of just how the immune system helps tumor cells proliferate and avoid immune detection led to rapid advances in immune-based targeting of cancer and its microenvironment. With this came the understanding that both “passive” (eg, infusing with antibodies or cytokines) and “active” (eg, vaccines) immunotherapies would be paramount for long-term tumor control or for complete elimination of tumors.8
An important and fairly successful outcome of this new wave of thinking has been the tumor-specific monoclonal antibodies that target specific antigens on cancer cells. Several of these antibodies have already been approved by the FDA and are being used as standard treatment in numerous cancer types ().
THE SCIENCE BEHIND I-O
The biggest advantage of the current immune therapies is that they stimulate the patient’s immune system to take charge and the proteins being targeted are not organ-specific. This broadens the scope of the therapy for use in multiple tumor types. While monoclonal antibodies, which target a specific antigen on a cancer cell, have proven successful in some tumor types, the effect is transient and cure rates are low, most likely due to a compromised immune system. The challenge with antibodies is maintaining a persistent memory response.
While T-cells persist longer, the antibody memory response is restricted to a single clone or a few clones, which allows tumor escape.8 The newly approved I-O agents are designed to overcome this weakness, raising the possibility of ideal combination immunotherapies.
Usually, the amplitude and quality of an immune response by T cells is a result of the balance between co-stimulatory and inhibitory (immune checkpoint) signals. The immune checkpoints help maintain homeostasis and prevent auto-immunity. However, to avoid immune recognition, tumors dysregulate these checkpoints. Two of the most widely studied inhibitory immune checkpoint receptors in oncology are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1).9 So far, 3 antibodies that target these receptors have been FDA-approved: ipilimumab (CTLA-4 inhibitor) for metastatic melanoma, and pembrolizumab and nivolumab (both PD-1 inhibitors) for metastatic melanoma with disease progression on ipilimumab (). It’s important to note that several other checkpoint inhibitor receptors are expressed on T cells, and molecules targeting these receptors and their ligands are also being evaluated.
Several drug combination therapies are currently in different stages in clinical trials and are providing encouraging results. A phase 1 trial with dual T-cell checkpoint inhibitors ipilimumab and nivolumab (targeting CTLA-4 and PD-1, respectively) presented promising 2-year survival rates in patients with advanced melanoma.10 Numerous other combinations—with dual checkpoint inhibitors, T-cell inhibitors with immune activators, and with chemotherapy—are ongoing in a multitude of tumor types.5
FUTURE DIRECTIONS FOR I-O
1. Human papilloma virus. FDA website. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm172678.htm. Accessed January 12, 2015.
2. Provenge (sipuleucel-T). FDA website. http://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm210012.htm. Accessed January 12, 2015.
3. Provenge (sipuleucel-T). Provenge website.http://www.provenge.com/. Accessed January 12, 2015.
4. Pollack A. Dendreon, maker of prostate cancer drug Provenge, files for bankruptcy. The New York Times website. http://dealbook.nytimes.com/2014/11/10/dendreon-maker-of-prostatecancer-drug-provenge-files-for-bankruptcy/?_r=0. Published November 10, 2014. Accessed January 14, 2015.
5. Antonia SJ, Larkin J, Ascierto PA. Immunooncology combinations: a review of clinical experience and future prospects. Clin Cancer Res. 2014;20(24):6258-6268.
6. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
8. Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(suppl 8):viii6-viii9.
9. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.
10. Bath C. ASCO 2014: ipilimumab/nivolumab combination achieves long-term survival for patients with advanced melanoma. The ASCO Post website. http://www.ascopost.com/ViewNews.aspx nid=16293. Published June 6, 2014. Accessed January 22, 2015.
As several articles in this issue indicate, a big challenge in I-O is identifying the target population for each treatment to enrich the cohort and achieve maximum treatment efficacy. Efforts to monitor the programmed death-ligand expression in tumors have yielded mixed results, as highlighted in the commentary by Richard Joseph, MD, on page SP97. Efforts to characterize potential biomarkers are ongoing. Challenges include the sequence of therapies and the duration of treatment administration. Identifying biomarkers or alternate clinical endpoints to measure responses to these I-O agents could potentially address the question of treatment duration.