Immunotherapy: A Glimmer of Hope for Metastatic Prostate Cancer

Vishal Jindal

Disclosures

Chin Clin Oncol. 2018;7(6) 

In This Article

Vaccine Therapy

Sipuleucel-T (Provenge)

Sipuleucel-T is FDA approved cancer vaccine for prostate cancer. It is an autologous cellular immunotherapy, in which immune cells from host are in vitro activated against specific cancer antigens, to mount an immune response. In this vaccine, antigen presenting cell (APC) or dendritic cells are harvested with leukopheresis, these immune cells are incubated with fusion protein (PA2024) incorporating the antigens associated with prostate cancer, prostate acid phosphatase (PAP) and granulocyte-macrophage colony stimulating factor (GM-CSF).[1] After processing for 48 hours these activated immune cells are transfused back into patients to mount an immune response. Total 3 cycles are given to patients every 2 weekly and course was completed in 1 month.[2]

It was approved by FDA in 2010 after phase 3 trial results of Immunotherapy for Prostate Adenocarcinoma treatment (IMPACT).[3] In this study 512 patients with mCRPC (metastatic castration-resistant prostate cancer) were enrolled. The patients who received Sipuleucel-T had a median overall survival (OS) of 25.8 months as compared to 21.7 months with placebo. It was statistically significant and there was 22% reduction in relative risk for mortality. However, there was no significant improvement in progression free survival (PFS). IMPACT also revealed that the greatest benefit occurs in patients with lower disease burden. As in this trial there is no improvement in PFS, short-term outcome and level of prostate specific antigen (PSA) didn't decrease, concern was raised regarding efficacy of Sipuleucel-T. At that time, we were unfamiliar with immunotherapy, but later on multiple trials on immunotherapy have showed similar findings of improved long term outcome but no short term improvement.[4–6] It has been suggested that Sipuleucel-T slows the progression of disease over time, as it has to enhance the immune system and cause proliferation and activation of anticancer cytotoxic T cells. Therefore, this antitumor effect may not be apparent initially and may be considered as disease progression in short term.

To check the immune response after treatment with Sipuleucel-T, a study was conducted by Fong et al. In this study 37 men with localized surgically resectable prostate cancer were treated with Sipuleucel-T as neoadjuvant therapy prior to radical prostatectomy.[7] Surgical prostatectomy samples were evaluated for immune response. There was threefold increase in infiltration of CD4 and CD8 T cells as compared to pretreatment biopsy and twelve patients who didn't get Sipuleucel-T as neo-adjuvant chemotherapy did not have similar immune response. This suggest sipuleucel-T mobilize T cells against the prostate cancer.

Given its OS benefit, enhanced immune response and favorable toxicity profile it should be a good option for patients with asymptomatic or minimally symptomatic mCRPC. However full three dose treatment is not cost effective,[8] require lot of coordinated effort for leukopheresis and sample transportation, with no benefit in PFS and short term outcome. Alone Sipuleucel-T doesn't seem to be have bright future, but in combination with chemotherapy, hormonal therapy or radium 223 it may have better outcomes.[9–12] Currently lot of early phase studies are going on individual and combination therapies of Sipuleucel-T, which have been summarized in Table 1.

PROSTVAC (PSA-TRICOM)

PROSTVAC is a prostate specific viral recombinant antigen targeted vaccine. Basically it has combination of two viral factors—immunologic priming agent "Vaccinia" and immunologic boosting agent "Fowlpox".[13] Each vector carries for PSA and three immunologic molecules-B7.1 (costimulatory molecule for T cells), ICAM-1 (intracellular adhesion molecule 1) and LFA-3 (lymphocyte function associated antigen 3).[14] Virus infects the APCs and induces presentation of tumor associated antigens. It promotes cell surface protein expression on APC and lead to activation and proliferation of T cells. Enhanced T cell function lead to aggravated immune response and promote degradation of cancer cells.[15] PROSTVAC enhances the avidity of T cells 100 folds,[16] this is significant as higher avidity lead to rapid activation of T cells with even minimal amount of antigen presentation. As cancers suppress the immune system, this property is more helpful to have tumor lysis effect. In this patient receive priming dose on day 1 and then subsequently booster vaccine on day 14, 28 and then monthly until disease progression.

Various studies have shown the immune response of PROSTVAC. One trial has shown the twofold increase in PSA specific T cell response in 57% of patients.[17] In a phase 2 trial[14] of PROSTVAC vs. control vector, it has been shown the improvement in OS. In PROSTVAC arm survival improved to 25.1 vs. 16.6 months in placebo control vector but the decline in PSA was minimal. Phase 3 multicentric study (NCT01322490) of PROSTVAC with or without GM-CSF vs. placebo in patients with mCRPC has recently been concluded and results are eagerly awaited.

Some of the early phase studies of PROSTVAC is going on which are summarized in Table 2.

GVAX

It is a cancer vaccine consists of two allogeneic irradiated prostate cancer cell lines LNCap and PC-3 which express GM-CSF.[18] Phase 1 and phase 2 studies showed promising results. In one study done to evaluate immunogenicity of GVAX on chemotherapy naïve mCRPC patients.[19] Patients were distributed in three groups, radiotherapy alone, GVAX high dose boost and GVAX low dose boost. The OS was 26.2, 34.9 and 24 months respectively. This vaccine in early studies was well tolerated with minimum autoimmune toxicities and improved patient survival. After that two phase 3 trials were conducted VITAL-1 and VITAL-2 which were prematurely terminated due to no therapeutic effect and increase in mortality.[20,21]

DCVAC/PCa

In this autologous vaccine, dendritic cells are obtained by leukopheresis and exposed to killed prostate cancer cells which stimulates patient's lymphocytes when they are reinjected into his body. In a phase 1/2 trial 25 patients with mCRPC received DCVAC vaccine with docetaxel. Patients also received Toll like receptor agonist to enhance immune system and cyclophosphamide to reduce regulatory T cells. The median OS was 19 months in patient who got DCVAC vaccine, whereas predicted OS was 11.8 months with Halabi nomogram and 13 months with MSKCC nomogram.[22] After success of phase 1/2 trial, a global Phase 3 trial was started named as VIABLE trial. In this trial DCVAC/PCa with first line chemotherapy for mCRPC is studied. The results of study are awaited.[23]

ProstAtak

It is based on gene transfer technology, via adenoviral vector, herpes simplex virus thymidine kinase is transferred to prostate cancer cells. Along with ProstAtak, radiation therapy and valacyclovir are also given. Radiation therapy will destroy the tumor and due to ProstAtak there will be enhanced immune response against cancer cells. If given in newly diagnosed and localized prostate cancer, it may prevent recurrence also. In a phase 1/2 trial,[24] 9 men with newly diagnosed localized prostate cancer got ProstAtak before radiotherapy, and after follow up of 11.3 years, 6 patients were alive and 3 patients passed away due to issues unrelated to prostate cancer. Now Phase 3 trial is going on to determine the immune response due to combination of ProstAtak and radiation therapy in intermediate to high risk localized prostate cancer. In this study patient will receive transrectal ultrasound guided injection of ProstAtak after 15 days to 8 weeks of radiation therapy. The primary end point of study is PFS and secondary end point will be OS and PSA progression (NCT01436968).

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