Dr. Susan Slovin, an expert on immunologic treatments for genitourinary malignancies, has crafted a well-written and comprehensive review of the state of the art in immunotherapy for prostate cancer. Her article highlights the differences between passive and active immunotherapy, discusses difficulties in monitoring an antitumor immune response, and reviews ongoing and completed clinical trials of both passive and active immunotherapy. While Dr. Slovin's article strikes an enviable balance between comprehensiveness and brevity, a small number of areas might prove worthy of further elaboration.
Immunotherapy With Monoclonal Antibodies
Dr. Slovin carefully reviews the development of a monoclonal antibody to prostate-specific membrane antigen (PSMA). This antibody was originally developed by the Bander group and evaluated in an unconjugated form (J591). Subsequently, evaluation has progressed through several robust phase II trials, including a number involving radiolabeled constructs (yttrium-90 and lutetium-177). While impressive targeting results have been obtained with J591-based monoclonal antibodies, the rate of objective clinical responses in patients with advanced disease has been somewhat underwhelming to date.
While moving to earlier disease stages is a logical extension of these studies, another potential approach to improve clinical efficacy might be to combine antibody-mediated targeting with active vaccination. Such an approach has shown synergistic efficacy in laboratory studies by the Reilly group, and is currently being extended to the breast cancer arena in an important phase II study initiated by Dr. Leisha Emens. Although dauntingly complex from a regulatory perspective, combinatorial studies using anti-PSMA monoclonal antibodies in combination with one of the active immunotherapy approaches for prostate cancer in the later stages of clinical development such as sipuleucel-T (Provenge) or GVAX might be considered in the near future.
It is also notable that a small number of additional targeted monoclonal antibodies are in early stages of development for prostate cancer. These agents include a fully human monoclonal antibody directed against prostate stem cell antigen (PSCA), being codeveloped by Merck and Agensys, Inc. Since PSCA appears to be relatively overexpressed on prostate metastases, PSCA might prove a particularly attractive target in men with advanced disease.
Another target currently under consideration in the clinic is the pro-inflammatory cytokine interleukin (IL)-6. Preclinical data show that IL-6 promotes the survival and proliferation of prostate cancer cells, and serum IL-6 levels are a marker for poor prognosis in men with advanced disease. The current clinical trial of this agent employs a combinatorial approach, administering mitoxantrone-based chemotherapy along with a chimeric monoclonal antibody developed by Centocor, Inc. An interesting facet of this trial is that the combinatorial approach is being explored early on, perhaps suggesting a wider acceptance of the notion that combination approaches will prove necessary to achieve clinical efficacy with immunotherapy.
Immune Checkpoint Blockade
Dr. Slovin provides an eloquent rationale for approaches combining immune checkpoint blockade with active immunotherapy in prostate cancer, and discusses an ongoing trial in which GVAX immunotherapy is combined with anti-CTLA-4 (ipilimumab) in men with hormone-refractory prostate cancer. It is perhaps notable that a similar combinatorial approach combining anti-CTLA-4 with a viral-based anti-PSA vaccine is currently enrolling patients at the National Cancer Institute. The principal investigator of this trial, Dr. James Gulley, and his colleague Dr. Philip Arlen have conducted a number of combinatorial trials with this vaccine vector, including combination with radiotherapy and antiandrogen administration.
While CTLA-4 blockade is currently the cornerstone of most of the ongoing combinatorial immunotherapy approaches, it is noteworthy that CTLA-4 knockout mice have a fairly significant phenotype, developing multisystem autoimmunity that proves fatal at 18 to 28 days of age. These data suggest that effective blockade of the CTLA-4/B7-1/2 axis might be associated with a measurable incidence of autoimmunity in the clinic; in fact, this has been observed. Thus, a number of additional checkpoints are under study in multiple laboratories, with the eventual goal of translation to combinatorial or single-agent studies in men with prostate cancer.
1. Nanus DM, Milowsky MI, Kostakoglu L, et al: Clinical use of monoclonal antibody HuJ591 therapy: Targeting prostate specific membrane antigen. J Urol 170:S84-S88, 2003.
2. Bander NH, Milowsky MI, Nanus DM, et al: Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol 23:4591-4601, 2005.
3. Wolpoe ME, Lutz ER, Ercolini AM, et al: HER-2/neu-specific monoclonal antibodies collaborate with HER-2/neu-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8+ T cell effector function and tumor-free survival in Her-2/neu-transgenic mice. J Immunol 171:2161-2169, 2003.
4. Emens LA, Reilly RT, Jaffee EM: Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity. Endocr Relat Cancer 12:1-17, 2005.
5. Lam JS, Yamashiro J, Shintaku IP, et al: Prostate stem cell antigen is overexpressed in prostate cancer metastases. Clin Cancer Res 11:2591-2596, 2005.
6. Gulley JL, Arlen PM, Bastian A, et al: Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11:3353-3362, 2005.
7. Arlen PM, Gulley JL, Todd N, et al: Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J Urol 174:539-546, 2005.
8. Chambers CA, Kuhns MS, Egen JG, et al: CTLA-4-mediated inhibition in regulation of T cell responses: Mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565-594, 2001.
9. Blansfield JA, Beck KE, Tran K, et al: Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28:593-598, 2005.
10. Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336-347, 2004.
11. Greenwald RJ, Freeman GJ, Sharpe AH: The B7 family revisited. Annu Rev Immunol 23:515-548, 2005.
12. Barber DL, Wherry EJ, Masopust D, et al: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682-687, 2006.
13. Day CL, Kaufmann DE, Kiepiela P, et al: PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350-354, 2006.
14. Huang CT, Workman CJ, Flies D, et al: Role of LAG-3 in regulatory T cells. Immunity 21:503-513, 2004.
15. Macon-Lemaitre L, Triebel F: The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology 115:170-178, 2005.
16. Murata S, Ladle BH, Kim PS, et al: OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. J Immunol 176:974-983, 2006.
17. Yewdell JW: The seven dirty little secrets of major histocompatibility complex class I antigen processing. Immunol Rev 207:8-18, 2005.
18. Yewdell JW: Immunology. Hide and seek in the peptidome. Science 301:1334-1335, 2003.
19. Warren EH, Vigneron NJ, Gavin MA, et al: An antigen produced by splicing of noncontiguous peptides in the reverse order. Science 313:1444-1447, 2006.
20. Engelhard VH: Creating new peptide antigens by slicing and splicing proteins. Nat Immunol 5:128-129, 2004.
21. Thomas AM, Santarsiero LM, Lutz ER, et al: Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med 200:297-306, 2004.
22. Hickman HD, Luis AD, Bardet W, et al: Cutting edge: class I presentation of host peptides following HIV infection. J Immunol 171:22-26, 2003.
23. Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-3094, 2006.
24. Johnson LE, Frye TP, Arnot AR, et al: Safety and immunological efficacy of a prostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP). Vaccine 24:293-303, 2006.
25. Arlen PM, Kaufman HL, DiPaola RS: Pox viral vaccine approaches. Semin Oncol 32:549-555, 2005.
26. Su Z, Dannull J, Yang BK, et al: Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 174:3798-3807, 2005.
27. Yoshimura K, Jain A, Allen HE, et al: Selective targeting of antitumor immune responses with engineered live-attenuated Listeria monocytogenes. Cancer Res 66:1096-1104, 2006.