Vaccine-Induced Specific Immune Response Offers an Avenue to Potentiate Responses to Immune Checkpoint Inhibitor Therapy

Cancer was once considered a disease of genetic origin, with hallmarks including sustained proliferation, resistance to apoptosis, the ability to promote angiogenesis, and the ability to promote invasion and metastasis. However, this view failed to take into consideration the dynamic nature of the interactions between a tumor and its microenvironment-not just the normal cells in the surrounding tissue, but also the immune system.

Advances in our understanding of the dual role that the immune system plays in cancer have 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. However, many patients with cancer do not respond to treatments with immune checkpoint inhibitors, in part due to the lack of tumor-infiltrating effector T cells.[1]

Cancer vaccines may help to prime patients for treatments with immune checkpoint inhibitors by inducing both effector T cell infiltration into the tumors and immune checkpoint signals. As such, combination therapy with a cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective anti-tumor immune responses.

In this article, we will explore the role of the immune system in cancer and discuss the potential of cancer immunotherapies that combine cancer vaccines and immune checkpoint inhibitors.

Quick review: tumor immunology

To understand how cancer vaccines may be used to potentiate other immunotherapies, it is important to understand the fundamentals of tumor immunology:

1. To initiate immunity, dendritic cells (DCs) must sample antigens derived from the tumor, which can be ingested in situ or delivered exogenously as part of a therapeutic vaccine, making DCs a potential site for therapeutic intervention. Upon antigen encounter, the DCs must also have to receive a suitable activation (or, maturation) signal, allowing them to differentiate extensively to promote immunity, as opposed to tolerance.

2. Next, tumor antigen-loaded DCs must generate protective T cell responses. The precise type of T cell response needed is unknown, but must include the production of CD8+ effector T cells with cytotoxic potential. DCs may also trigger antibody and natural killer/natural killer T (NK/NKT) cell responses, which may contribute to tumor immunity.

3. Finally, cancer-specific T cells must enter the tumor bed to perform their function. Here, there is the challenge of immune suppression. Presumably by skewing DC maturation, tumors may:

• Prevent immunization

• Trigger the “wrong” immune response, or

• Enable the local accumulation or expansion of regulatory T cells (Treg cells) that would oppose the activity of effector T cells.

Status of cancer vaccines

Cancer vaccines come in two formats: prophylactic and therapeutic. Prophylactic vaccines have been used with considerable success in preventing cancers of viral origin, such as hepatitis B virus (HBV) and human papillomavirus (HPV), where the etiologic agent is known. In contrast, the development of therapeutic vaccines has been problematic, with many promising phase II studies failing to show survival benefit in phase III trials.

The hypothesis behind therapeutic cancer vaccines originated with the discovery that patients with cancer can harbor CD8+ and CD4+ T cells specific for cancer/testis antigens or differentiation antigens expressed in their tumors. Vaccination might reasonably be expected to amplify the frequency and strength of these pre-existing responses, or perhaps induce de novo reactions. In addition, clinico-pathologic studies have demonstrated a strong association between prolonged patient survival and the presence of intra-tumoral CD3+ or CD8+ cytotoxic T cells and an interferon-gamma (IFN-γ) gene signature. If vaccination could trigger these types of T cell responses, then clinical benefit might be expected.

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

1. Sipuleucel-T (marketed as Provenge®) received FDA approval in April 2010 for the indication of advanced prostate cancer.[2] Originally assumed to be an autologous DC-based vaccine, sipuleucel-T is made up of an incompletely characterized, complex mixture of peripheral blood mononuclear cells (PBMCs) supplemented with a cytokine and tumor-derived differentiation antigen.

A phase III trial of sipuleucel-T showed little evidence of tumor shrinkage or delay in disease progression. By standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria, only one of the 341 patients in the active arm exhibited a partial response. However, the study did show a 4.1-month improvement in median overall survival (25.8 months vs 21.7 months). This survival benefit was deemed significant by the FDA in a patient population that has few, if any, other effective therapeutic options.[3]

2. Talimogene laherparepvec (T-VEC, marketed as Imlygic®) was approved by the FDA in October 2015 for treatment of melanoma lesions in the skin and lymph nodes.[4] T-VEC is a genetically modified live oncolytic herpes virus therapy that is injected directly into melanoma lesions, where it replicates inside cancer cells and causes apoptosis. Oncolytic virus therapy mediates tumor regression through two distinct mechanisms. First, many viruses possess an innate tropism for cancer cells where they can preferentially replicate and kill established tumor cells. Secondly, the dying tumor cells can serve as a target for cross priming tumor-specific immune responses to generate systemic anti-tumor immunity.[5]

The safety and efficacy of T-VEC were evaluated in a multi-center study of 436 patients with metastatic melanoma that could not be surgical removed. The study showed that 16.3 percent of study participants who received T-VEC experienced a decrease in the size of their melanoma lesions, lasting for at least six months, compared to 2.1 percent of study 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.[6]

Other oncolytic viruses that may be nearing approval in North American and Europe include pexastimogene devacirepvec (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.[7]

Challenges of Cancer Vaccines

There are a variety of challenges associated with the development of therapeutic cancer vaccines:

· The vaccine initially induces an immune reaction against the vaccine itself, not the tumor. As such, the immune system mainly recognizes “neo-antigens” from “passenger” mutations rather than shared antigens.

· The antigens are different for each tumor. Consequently, a therapeutic cancer vaccine would need to involve autologous tumor cells.

· Most immune-responsive tumors auto-vaccinate, but immune regulation prevents an effective response. Even if a vaccine enhances anti-tumor immunity, cells are unlikely to be suppressed in the tumor microenvironment.

Based on the foregoing issues, vaccines are unlikely to have a major anti-tumor effect in the absence of immune checkpoint control.

Immune Checkpoint Inhibitors: A Turning Point in Cancer Immunotherapy

Immune checkpoints refer to a plethora of inhibitory pathways in the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues. It is now clear that tumors co-opt certain immune checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens.[8]

T cell responses are regulated via multiple co-stimulatory and inhibitory interactions. T cell response to antigen is mediated by peptide-major histocompatibility complex (MHC) recognized by the T cell receptor. The B7 family of membrane-bound ligands binds both co-stimulatory and inhibitory receptors. Targeting cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and programmed cell death ligand-1 (PD-L1) inhibitory receptors has been a major clinical focus.[8]

In 2011, the FDA approved the first immune checkpoint inhibitor, ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4 antibody for the treatment of metastatic and non-resectable melanomas.[9] 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 approval from the FDA for the treatment of ipilimumab-refractory melanoma.[10] Pembrolizumab has also been approved as a single agent for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) whose tumors have high programmed cell death ligand-1 (PD-L1) expression, and nivolumab has also been approved for patients with metastatic squamous NSCLC who have progressed on or after platinum-based chemotherapy.[11]

Combining Cancer Vaccines with Immune Checkpoint Inhibitors

While immune checkpoint inhibitors represent a turning point in cancer immunotherapy, only about 10 to 50 percent of cancer patients with certain types of solid tumors have shown responses to treatments with immune checkpoint inhibitors. This has been attributed to properties of the tumor microenvironment, as well as a lack of tumor-infiltrating effector T cells.

On the other hand, cancer vaccines serve to enlarge the pool of tumor-specific T cells, as well as to activate tumor-specific T cells that are dormant.[12] While cancer vaccines have been shown to induce effector T cell infiltration into tumors, they need to overcome immune evasion to be fully effective.

Consequently, it has been suggested that combining an immune checkpoint inhibitor with a cancer vaccine may result in a synergistic effect on the anti-tumor immune response. This hypothesis has been supposed by multiple preclinical studies. Supported by data from those studies, a clinical trial to test the combination of GM-CSF-secreting cancer vaccine (GVAX) and nivolumab in patients with metastatic pancreatic cancer has been initiated (ClinicalTrials.gov identifier: NCT02243371). Another clinical trial testing the combination of GVAX and nivolumab as neoadjuvant and adjuvant therapies for resectable pancreatic cancer (ClinicalTrials.gov identified: NCT02451982) is currently recruiting participants, as well.

Conclusion
Cancer vaccine-based immunotherapy may help overcome the resistance of certain tumors to immune checkpoint inhibitors, while immune checkpoint inhibitors may enhance the efficacy of cancer vaccine therapies. This hypothesis remains to be proven in phase III clinical trials, but combination therapy with cancer vaccines and immune checkpoint inhibitors may be the next breakthrough in cancer therapy.

[1] 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.

[2] National Cancer Institute. FDA Approval for Sipuleucel-T. Available at https://www.cancer.gov/about-cancer/treatment/drugs/fda-sipuleucel-T.

[3] Kantoff PW, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

[4] 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.

[5] Rehman H, et al. Into the clinic: Talimogene laherparpvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy.

[6]Andtbacka RHI, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780-2788.

[7] Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Sci. 2016;107:1373-1379.

[8] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.

[9] Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723.

[10] 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.

[11] Brahmer J, et al. Nivolumab versus docetaxel in advanced squamous non-small-cell lung cancer. N Engl J Med 2015;373:123-135.

[12] van der Burg SH, et al. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nature Reviews Cancer. 2016;16:219-233.

Nina Baluja, M.D. is the Senior Medical Director for Medical Services, Premier Research