THERAPEUTIC VACCINES - Exploring the Potential of Combining Cancer Vaccines With Immune Checkpoint Inhibitor Therapy

INTRODUCTION

Reality has largely failed to meet expectation when it comes to the development of therapeutic cancer vaccines. Despite considerable efforts, the clinical translation of vaccines into efficacious cancer therapies has been challenging for decades. However, advances in our understanding of tumor immunology are rekindling interest in cancer vaccines, particularly in combination with breakthrough immunotherapies, such as immune checkpoint inhibitors.

CANCER VACCINES TODAY

Cancer vaccines can be either prophylactic or therapeutic. Prophylactic vaccines are designed to prevent disease in healthy individuals, and have been used in preventing cancers of viral origin, such as hepatitis B virus (HBV) and human papillomavirus (HPV). In contrast, the development of therapeutic vaccines has been problematic, with many promising Phase 2 studies failing to show survival benefit in Phase 3 trials.

To date, only two therapeutic cancer vaccines have been approved by the FDA: sipuleucel-T and talimogene laherparepvec.

-Sipuleucel-T (marketed as Provenge^®) received approval in April 2010 for advanced prostate cancer.¹ In a Phase 3 trial of sipuleucel-T, only one of the 341 patients in the treatment arm exhibited a partial response by standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria. However, the study showed a 4-month improvement in overall survival. The FDA deemed this survival benefit to be significant in a patient population that has few, if any, other effective therapeutic options.² Unfortunately, market uptake of this vaccine has been low.

-Talimogene laherparepvec (T-VEC, marketed as Imlygic^®), a genetically modified live oncolytic herpes virus therapy, was approved in October 2015 for treatment of melanoma lesions in the skin and lymph nodes.³ T-VEC is injected directly into the lesions, where it replicates inside cancer cells and causes cell death. T-VEC was evaluated in a multi-center study of 436 patients with unresectable metastatic melanoma. The study showed that participants who received T-VEC experienced a significant (and lasting) decrease in the size of their melanoma lesions, compared to participants who received comparator therapy. However, T-VEC has not been shown to improve overall survival, or to have an effect on melanoma that has metastasized to the brain, bone, liver, lungs, or other internal organs.⁴

Oncolytic virus therapies like T-VEC may be the next breakthrough in cancer treatment following the recent success in immunotherapy using immune checkpoint inhibitors. Oncolytic virus therapy mediates tumor regression through two distinct mechanisms. First, many viruses possess an affinity for cancer cells where they can preferentially replicate and kill established tumor cells. Secondly, the dying tumor cells can serve as a target for tumor-specific immune responses to generate systemic anti-tumor immunity.⁵ Other oncolytic viruses that may be nearing approval in North American and Europe include pexastimogene de-vacirepvec (a vaccinia virus) for hepatocellular carcinoma, GM-CSF-expressing adenovirus CG0070 for bladder cancer, and palavered (a wild-type variant of reovirus) for head and neck cancer.⁶

CHALLENGES OF DEVELOPING THERAPEUTIC CANCER VACCINES

The issues that have hampered the development of therapeutic cancer vaccines are related to both the nature of vaccines and the fundamentals of tumor immunology.

-The vaccine initially induces an immune reaction against the vaccine itself, not the tumor.

-Each tumor has different antigens. As a result, a therapeutic cancer vaccine would need to involve autologous tumor cells.

-Most immune-responsive tumors autovaccinate, but immune regulation prevents an effective response. Due to these challenges, vaccines are unlikely to have a major anti-tumor effect without control of immune checkpoints.

IMMUNE CHECKPOINT INHIBITORS: A REVOLUTION IN CANCER THERAPY

Immune checkpoints refer to the myriad inhibitory pathways in the immune system that maintain self-tolerance and modulate immune responses. With advances in our understanding of tumor immunology, it is now clear that tumors can co-opt immune checkpoint pathways as a mechanism of immune resistance. This has led to the development of immune checkpoint inhibitors, cancer therapies that prevent cancer cells from turning off T cells, enabling those T cells to infiltrate the tumor and stop it from growing.

The first immune checkpoint inhibitor, ipilimumab, was approved by the FDA in 2011 for the treatment of metastatic and non-resectable melanomas.⁷ In 2015, pembrolizumab (marketed as Keytruda^®) and nivolumab (marketed as Opdivo^®) were the first of the anti-programmed cell death (PD)-1 pathway family of checkpoint inhibitors to gain accelerated FDA approval for the treatment of ipilimumab-refractory melanoma.⁸ Since then, both pembrolizumab and nivolumab have also been approved for metastatic non-small cell lung cancer (NSCLC) indications.⁹

CANCER VACCINES MAY POTENTIATE RESPONSES TO IMMUNE CHECKPOINT INHIBITOR THERAPY

While immune checkpoint inhibitors have revolutionized cancer therapy, they are only effective in 10 to 50 percent of patients with select solid tumors. Many patients with cancer do not respond to immune checkpoint inhibitor therapy, in part due to the lack of tumor-infiltrating effector T cells.¹⁰

This is where cancer vaccines may play a critical role. Cancer vaccines may help to prime patients for immune checkpoint inhibitor therapy by inducing both effector T cell tumor infiltration and immune checkpoint signals. In turn, immune checkpoint inhibitors may boost the potency of cancer vaccine therapies. Thus, combination therapy with a cancer vaccine and an immune checkpoint inhibitor has the potential to synergistically induce more effective anti-tumor immune responses. This hypothesis has been supported by multiple preclinical studies, and various clinical trials are currently underway.

THE FUTURE OF THERAPEUTIC CANCER VACCINES

The renewed interest in cancer vaccines doesn’t end with immune checkpoint inhibitors. In fact, investigators are also exploring whether vaccines can potentiate conventional treatment, including surgery, radiation, and chemotherapy. Only time will tell, but there is no doubt that cancer immunotherapy has come of age, and cancer vaccines will likely play role in the future of cancer treatment.

REFERENCES

1. National Cancer Institute. FDA Approval for Sipuleucel-T. Available at https://www.cancer.gov/aboutcancer/treatment/drugs/fda-sipuleucel-T.
2. Kantoff PW, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
3. U.S. Food and Drug Administration. FDA approves first-of-its-kind product for the treatment of melanoma, October 27, 2015. Available at https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm469571.htm.
4. Andtbacka RHI, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780-2788.
5. Rehman H, et al. Into the clinic: Talimogene laherparpvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy.
6. Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Sci. 2016;107:1373-1379.
7. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723.
8. Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther. 2015;37(4):764-782.
9. Brahmer J, et al. Nivolumab versus docetaxel in advanced squamous non-small-cell lung cancer. N Engl J Med 2015;373:123-135.
10. Kleponis J, Skelton R, Zheng L. Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors. Cancer Biol Med. 2015;12(3):201-208.

Dr. Nina Baluja is currently Senior Medical Director, Medical Services for Premier Research, where she performs medical and safety monitoring on clinical research projects and provides strategic guidance on protocol development, study design, regulatory filings, and study execution. She has more than 15 years of clinical research, medical marketing, and drug safety experience in the CRO and pharmaceutical fields. Prior to joining Premier Research in 2017, Dr. Baluja was Senior Medical Director at PRA Health Services. Before that, she oversaw global regulatory consulting at PPD and worked extensively in the pharma sector in positions that included Medical Scientific Advisor at Boehringer-Ingelheim, Associate Medical Director at Wyeth Pharmaceuticals, and Trial Delivery Manager at AstraZeneca. Dr. Baluja’s areas of specialty include oncology, hemato-oncology, and rare diseases. She has significant clinical development regulatory experience, having prepared and participated in numerous scientific meetings with the FDA, EMA, and Health Canada. She earned her MBBS from Pune University in India and her Master’s in Surgical Oncology from Bombay University.