Cancer Immunotherapy: Sipuleucel‐T and Beyond

Abstract

In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4+ and CD8+ T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor-associated antigens aimed at stimulating effector T-cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer.

Immunotherapy against cancer: A comprehensive review

“…A vaccine belongs to this type, called Vitespen, is a peptide-based vaccine which uses an autologous tumour-derived heat shock (chaperone) protein; glycoprotein (gp) 96-peptide complex (HSPPC-96) as an antigen (Hammerstrom et al, 2011). In phase-III clinical studies against melanoma and locally advance renal cell carcinoma, Vitespen has failed to provide a significant increase in overall survival rates and showed no overall benefit in recurrence-free survival (Wood et al, 2008;Testori et al, 2008).…”

“…In phase-III clinical studies against melanoma and locally advance renal cell carcinoma, Vitespen has failed to provide a significant increase in overall survival rates and showed no overall benefit in recurrence-free survival (Wood et al, 2008;Testori et al, 2008). However, these studies showed an insignificant benefit with patient in earlier stages and also the subgroup analysis indicated that patients with higher doses of Vitespen survived longer than ones with the lower doses (Hammerstrom et al, 2011).…”

“…Even though the use of autologous tumour cells eliminates the antigen selection problem by providing the advantage of targeting the individual's own tumour associated antigens, this approached has been abandoned due to the motion that this kind of vaccine would not raise an effective anti-cancer immune response since it was not pre-existing in the first place (Hammerstrom et al, 2011). Furthermore, the high complexity of the vaccine preparation for each individual patient additionally instigated the abandoning of this approach (Mellman et al, 2011).…”

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

“…Such vaccines follow two purposes, namely priming antigen-specific T cells and reprogramming memory T cells by transforming them from the immunosuppressive to the immunostimulating and cytotoxic phenotype. Dendritic cells (DCs) are very potent antigen presenting cells and thus essential in generation of immune responses, and they therefore represent valuable targets and vectors for cancer vaccination [280][281][282][283][284][285][286][287][288][289][290][291][292][293].…”

Snake Venom: A Potent Anticancer Agent

“…It mainly focuses on empowering the immune system to overcome the tumor rather than producing widespread cyto-toxicity to kill tumor cells. Many anti-cancer immuno-therapies use tumor-associated antigens as vaccines in order to stimulate immune response against cancer cells (Hammerstrom et al, 2011). Since, the tumor invokes multiple immunesuppressive mechanism to defend itself, hence, we need to overcome it so as to make immunotherapy a suitable option for treating cancer (Berzofsky et al, 2012).…”