Prostate cancer as a model for tumour immunotherapy

Abstract

Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context.

Figure 1. Clinical states of prostate cancer and current therapeutic interventions

For most patients, prostate cancer is a slowly progressive disease. Most patients are diagnosed with localized disease, and treated with either radiotherapy or surgery. However, a substantial fraction of these men later develop a rising prostate-specific antigen (PSA) level in the absence of radiographically detectable lesions, a state known as biochemical recurrence. Men with biochemically recurrent disease can be either monitored or treated with androgen ablation (surgical or chemical castration). Eventually, a fraction of men develop radiographically detectable metastatic disease; it is in the setting of castration-resistant metastatic disease that most immunotherapy approaches for prostate cancer have been tested.

Figure 2. Examples of antigen-specific immunotherapy for prostate cancer

a ∣ The ProstVac VF ‘vaccine’ consists of a DNA plasmid encoding the target antigen, prostate-specific antigen (PSA), and a series of three co-stimulatory molecules (lymphocyte function-associated antigen 3 (LFA3), CD80 and intercellular adhesion molecule 1 (ICAM1)). The plasmid cassette is incorporated into a poxvirus backbone in a ‘packaging’ cell line, giving a final vaccine product. In this approach, a vaccinia virus-based prime is followed by a fowlpox virus-based boost. The viral vectors are injected intradermally, where they probably infect the patient’s epithelial cells. This in turn leads to epithelial cell death, following which the cellular debris (including the target antigen PSA) is taken up by host antigen-presenting cells (APCs) and presented to host CD4⁺ and CD8⁺ T cells. A second potential mechanism for antigen presentation involves direct infection of APCs, including the Langerhans cells in the skin. The incorporation of CD80 into the viral vector facilitates the activation of T cells, through the provision of a co-stimulatory signal for T cell activation. LFA3 and ICAM1 are adhesion molecules; in this context their vector-driven expression on APCs provides additional co-stimulation to facilitate T cell activation. b ∣ Sipuleucel-T immunotherapy is similar to a dendritic cell (DC) vaccine and is based on cells from a patient-derived leukopheresis product. These cells are sent to a central processing facility where monocytes are enriched by density–gradient centrifugation. These monocytes are incubated for 36–44 hours with a specific fusion protein, coupling granulocyte–macrophage colony-stimulating factor (GM-CSF) to the target antigen, in this case prostatic acid phophatase (PAP). In this approach, GM-CSF targets the fusion protein to immature DCs and enhances subsequent DC maturation. Following incubation, the product is sent to the clinic where it is administered intravenously. Once in the patient, the patient’s immature monocytes are thought to mature to fully competent APCs, presenting PAP peptides to the host immune system in a manner that activates CD4⁺ and CD8⁺ T cells. c ∣ J591 is an antigen-specific approach using a humanized monoclonal antibody specific for prostate-specific membrane antigen (PSMA). Although early trials used unlabelled antibody, current trials involve ¹⁷⁷Lu-labelled J591, a β-ray emitter with a half-life and path-length favourable for radiotherapy and immunotherapy. Here, the antibody specifically targets the radioactive isotope to the target tissue, where tumour cell death is mediated by irradiation. CDR, complementarity-determining region; TCR, T cell receptor.

Figure 3. Immunotherapy for prostate cancer not directed towards a single tumour antigen

a ∣ In a cell-based immunotherapy approach, allogeneic cancer cell lines specific for a particular cancer type are engineered to secrete granulocyte–macrophage colony-stimulating factor (GM-CSF), which first recruits antigen-presenting cells (APCs), such as dendritic cells (DCs), and T cells (not shown here) to the injection site. The injected vaccine tumour cells undergo necrosis, and cellular debris is taken up by the recruited DCs. Next, the DCs must mature to effectively prime an immune response; GM-CSF secreted by the vaccine cells probably has a role here as well. In the prostate GVAX approach, the injected cancer cells are allogeneic with respect to treated patients, so this immunotherapy relies on cross-presentation to prime a CD8⁺ T cell antitumour immune response. The prostate cancer cell lines used are LNCaP and PC3, which are androgen-sensitive and castration-resistant prostate cancer cells, respectively. b ∣ The immune checkpoint blockade approach is exemplified by antibodies specific for cytotoxic T lymphocyte antigen 4 (CTLA4) (such as ipilimumab and tremelimumab), which block the immunosuppression mediated by the interaction between CD80 and CD86 (on APCs) and CTLA4 (on CD8⁺ and CD4⁺ T cells). A second important immune checkpoint, mediated by the interaction between programmed cell death 1 (PD1) on T cells and its ligand B7-H1 (also known as PDL1) on either APCs or tumour cells, has been the subject of several recent early phase clinical trials. The interaction between lymphocyte activation gene 3 (LAG3) on T cells and MHC class II molecules on APCs is also inhibitory; indeed, CD8⁺ T cell unresponsiveness may depend on the interaction of several, non-overlapping checkpoints. TCR, T cell receptor.