Proposed mechanisms of action for prostate cancer vaccines

Abstract

Prostate cancer is responsible for the deaths of more than 33,000 American men every year. Once this disease has become metastatic, there is no curative treatment. Alternative therapies to chemotherapy and radical prostatectomy are being increasingly explored. Prostate cancer vaccines--which trigger a tumour-specific cytotoxic-T-lymphocyte-mediated immune attack by the patient's immune system--have been investigated in clinical trials with modest, yet encouraging, results. When developing and administering prostate cancer vaccines, it is critical to consider how vital parameters, such as the stage of disease progression and the nature of adjuvant therapies, could influence treatment outcome. Of particular interest are current and future strategies for diminishing the activity of regulatory T lymphocytes.

Schematic 1. Proposed mechanism(s) of ProstVac VF action

Pathway 1: VV infects immature and/or mature DCs which travel to draining lymph nodes and express co-stimulatory proteins and MHC class I/PSA (1a) where they trigger activation and proliferation of PSA-specific CD8+ T lymphocytes (1b), which then circulate to tumor sites and kill tumor cells through programmed cell death (PCD) (1c). Pathway 2: VV infects somatic cells (2a) which then directly activate PSA-specific CTLs (2b), and NK cells (2b’) , which then induce PCD of somatic cells (2c and 2c’) which are then taken up by DCs that are activated by viral components to mature and cross-present PSA (2d). These DCs further stimulate PSA-specific CTL activation (2e) that cause PCD of tumor cells (2f).

Schematic 2. Proposed mechanism of Ad5-PSA action

Ad5-PSA directly infects immature DCs (a receptor-mediated process) (1a) resulting in DC maturation and presentation of MHC class I in association with PSA epitopes (2). In addition, Ad5-PSA infects somatic cells (1a’) which are then recognized (1b) and killed (1c) by NK cells through an E1A-independent pathway involving NKG2D/stress-induced protein interaction. NK-mediated killing results in apoptotic bodies (1d) being taken up by immature DCs (1e) and promoting DC maturation and presentation of PSA epitopes in association with MHC class II (2). In the lymph node, activated DCs trigger activation and proliferation of PSA-specific CD8+ T lymphocytes (3a) possibly with the aid of activated CD4+ T lymphocytes (3b) supplying additional IL-2 (3c). PSA-specific CTLs then circulate to tumor sites and kill tumor cells through PCD (4).

Schematic 3. Proposed mechanism of action of sipuleucel-T

Infused antigen presenting cells (sipuleucel-T) travel to the spleen where they secrete PAP-GM-CSF fusion protein that attracts splenic DCs and stimulates DC maturation (through autocrine (1a) and paracrine (1b) GM-CSF function) and presention of PAP epitopes in association with MHC class II (1b). Splenic DCs and/or sipuleucel-T APCs activate CD4+ T lymphocytes (2) which then provide IL-2 (3b) to PAP-specific CD8+ T lymphocytes (3a) which then mediate PCD of tumor cells (4).

Schematic 4. Proposed mechanism of action of GVAX-PCa

Irradiated allogeneic tumor cells (LNCAP + PC-3) secrete recombinant GM-CSF which has the triple role of chemotactically attracting immature DCs (1a), inducing DC maturation (2) and cross-presentation of proteins from apoptotic GVAX-PCa (1b, 1c, 2). Irradiated tumor cell apoptotic bodies (1b) and are taken up by DCs (1c) and B cells (1d) and also contribute to DC maturation (2). Mature DCs activate CD4+ T lymphocytes (3a) and CD8+ T lymphocytes (3b). Activated CD4+ T lymphocytes further stimulate B lymphocyte activation (4a) and provide IL-2 for CD8+ T lymphocytes (4b). B lymphocytes produce TAA-specific antibodies to cell-surface proteins that result in ADCC or complement-mediated tumor cell death (specific details not shown) (5a). Activated CD8+ T lymphocytes then kill tumor cells through recognition of MHC class I in association with TAA epitopes (5b).

Schematic 5. Proposed mechanism of action of DNA cancer vaccines

GM-CSF, which is co-injected with pDNA/TAA, attracts immature DCs (primarily Langerhans cells) and induces their maturation (1a). Simultaneously, pDNA/TAA transduce the DC (1b) and the DC expresses TAA epitopes in association with MHC class I and stimulates TAA-specific CD8+ T lymphocyte activation in the draining lymph node (2a). It is likely that some TAA epitopes are expressed in association with MHC class II resulting in activation of CD4+ T lymphocytes (2b) that provide further help (IL-2) for TAA-specific CD8+ T lymphocytes (3) which are then capable of killing tumor cells by PCD (4).

Schematic 6. Proposed mechanism of action of gene-mediated cytotoxic immunotherapy

Tumor cells are transduced with AdV-tk (1) and convert a pro-drug to a toxic drug that induces an immunogenic cell death (2). Apoptotic tumor cells are taken up by immature DCs (3a) and B lymphocytes (3b) and contribute to DC maturation (4). Mature DCs activate CD4+ T lymphocytes (5a) and CD8+ T lymphocytes (5b). Activated CD4+ T lymphocytes further stimulate B lymphocyte activation (6a) and provide IL-2 for CD8+ T lymphocytes (6b). B lymphocytes produce TAA-specific antibodies to cell-surface proteins that result in ADCC or complement-mediated tumor cell death (specifics not shown) (7a). Activated CD8+ T lymphocytes then kill tumor cells through recognition of MHC class I in association with TAA epitopes (7b).