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Developing a Rational Tumor Vaccinetherapy for Renal Cell Developing a Rational Tumor Vaccine Therapy for Renal Cell Carcinoma: Immune Yin and Yang Marc S. Ernstoff,1, 2 , 3,11 Todd S. Crocenzi,13 John D. Seigne,3,6,7 Nancy A. Crosby,1, 2 Bernard F. Cole,3,10,12 Jan L. Fisher,1, 2 Jill C. Uhlenhake,1, 2 Diane Mellinger,1, 2 Cathy Foster,1, 2 ConradJ. Farnham,3 Kathleen Mackay,3 Zbigniew M. Szczepiorkowski,3,4,5,11Susan M.Webber,4,5 Alan R. Schned,3,5 Robert D. Harris,8 Richard J. Barth, Jr.,3,7,11John A. Heaney,3,6,7 and Randolph J. Noelle3,9,11,12 Abstract In patients with progressive malignancy, the natural balance between proinflammatory (Yang) and inhibitory (regulatory or Yin) immune pathways is disrupted and favors cancer-specific immune suppression. Therapy with interleukin 2 (IL-2) can mobilize immune effector cells that recognize and destroy cancer. High-dose IL-2 is the only therapy that has consistently induced complete durable remissions in patients with metastatic renal cell carcinoma (RCC) but only in a few of them. The lack of benefit in most metastatic RCC patients is likely due to the ineffective manipulation of other immune circuits critical in regulating tumor cytotoxic pathways. The limited clinical activity of IL-2, RCC vaccines, and other immune therapies to date leads us to postulate that effective clinical treatment strategies will need to simultaneously enhance proinflammatory pathways and disrupt regulatory pathways. We present preliminary studies in RCC patients to highlight the complexity of the regulatory pathways and our approach to shifting the balance of proinflammatory and regulatory immune pathways using dendritic cell ^ tumor lysate vaccine followed by cytokine therapy. Until recently, the most successful therapy for metastatic renal induce complete durable remissions but only in few metastatic cell carcinoma (RCC) has been that of single-agent, high-dose RCC patients.The reason why IL-2 therapy fails in most interleukin 2 (IL-2; ref.1).The addition of other proinflamma- metastatic RCC patients may be explained, in part, by a tory agents, such as IFN-a, or adoptive cellular therapy with persistent imbalance between proinflammatory/stimulatory ex vivo expanded autologous effector cells, such as lymphokine- (Yang) and regulatory (Yin) pathways (11–13). activated killer cells or tumor-infiltrating lymphocytes, to IL-2 The CD8+ CTLs mediate tumor destruction and represent a has failed to significantly improve clinical outcome compared common pathway for many immunotherapeutic approaches. with IL-2 alone (1–5).Vaccine strategies have also had limited CD8+ tumor-specific T cells naturally exist in the lymphocyte benefit for patients with metastatic RCC (6).Recently memory compartment and can be identified in the peripheral introduced ‘‘directed therapies,’’ such as bevacizumab, sorafe- blood of cancer patients (14, 15).Memory CD8 + T lymphocytes nib, sunitinib, and temsirolimus, have had an effect on the consist of a heterogeneous mixture of two lineage groups of survival of metastatic RCC patients but rarely induce durable cells that evolve in parallel: central memory CD8+ T cells, which complete remissions (7–10). recirculate through lymph nodes, and effector memory CD8+ T Immunotherapy with high-dose IL-2, which mobilizes cells, which are mostly found in peripheral tissues (16).Central immune effector cells that recognize and destroy cancer, can memory and effector memory T-cell responses can be enhanced by dendritic cell (DC)–presenting tumor antigens (17).Thus, DC vaccination approaches may help to optimize antitumor CTL generation. Authors’ Affiliations: 1Medical Oncology Immunotherapy Group, 2Section of Tolerogenic pathways that involve regulatory cells are a 3 4 Hematology/Oncology, Norris Cotton Cancer Center, Cell Therapy Center, mechanism of tumor-specific anergy (18–20).CD4 +CD25+high 5Department of Pathology, 6Section of Urology, 7Department of Surgery, 8Department of Diagnostic Radiology, 9Department of Microbiology and regulatory T (Treg) cells function in a non–antigen-specific Immunology, 10Section of Biostatistics and Epidemiology, Department of Family manner through T cell to T cell contact or other contact- and Community Medicine, and 11Immunotherapy Program, Dartmouth-Hitchcock dependent mechanisms or through expression of immunosup- 12 À Medical Center, Lebanon, New Hampshire; Dartmouth Medical School, Hanover, pressive cytokines.CD8 +CD28 suppressor T (T ) cells inhibit 13 s New Hampshire; and Earle A. Chiles Cancer Research Center, Portland, Oregon immune responses via cell-to-cell interactions or using antigen- Received 8/17/06; revised 11/10/06; accepted 11/16/06. + Grant support: NIH grant RO1CA5648 and Berlex, Inc. presenting cells as a bridge to the CD4 T helper cell in an Presented at the Second Cambridge Conference on Innovations and Challenges in antigen-specific, MHC-restricted manner (21–23).Under Renal Cancer, March 24-25, 2006, Cambridge, Massachusetts. experimental conditions in murine models, tumor-DC vacci- Requests for reprints: Marc S. Ernstoff, Dartmouth-Hitchcock Medical Center, nations can overcome tolerance and enhance therapeutic Lebanon, NH 03756. Phone: 603-650-5534; Fax: 603-650-7791; E-mail: [email protected]. outcome (24).IL-2 and IFN- a can also contribute in over- F 2007 American Association for Cancer Research. coming these regulatory pathways (25, 26).Other inhibitory doi:10.1158/1078-0432.CCR-06-2064 loops include both natural killer T cells and a subpopulation of www.aacrjournals.org 733s Clin Cancer Res 2007;13(2 Suppl) January 15, 2007 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2007 American Association for Cancer Research. inhibitory DCs (27, 28).The contribution of each of these Regulatory Pathways andTs Cells regulatory compartments to tumor tolerance in the cancer + patient is currently unknown (29, 30). Over the past few years, disruption of the CD4 Treg function The lack of ability of cancer patients’ CTLs to mount a through the blocking of CTLA-4 has been a clinical focus of complete response against tumor (anergy) may also be due to immunotherapy.It is not clear whether anti–CTLA-4 antibody ~ ~ the loss of the T-cell receptor chain (TCR ), defective blockade directly works on the Treg cells or by blocking negative signalingdownstreamfromTCR~, and/or activation of signals to effector T cells.CTLA-4 molecule is constitutively + inhibitory pathways by regulatory cells (31, 32).Some of expressed on CD4 Treg cells and competes with CD28 (a T-cell these defects can be corrected by subsequent cytokine signals, stimulatory receptor) to bind to B7.1/B7.2 on antigen-present- including IL-2 (33).Agents that exploit proinflammatory acti- ing cells (45).When CTLA-4 is disabled, it is believed that CTLs vities that both enhance CTL function and disrupt regulatory are released from inhibition and the regulatory effects of Treg pathways may synergistically act in causing immune-mediated cells are diminished.Disabling CTLA-4 can be achieved by a tumor destruction.We hypothesize that immunotherapy using blocking antibody (anti–CTLA-4; ref.46).Preliminary clinical mature DC vaccine administered intranodally, IL-2, and IFN-a trials of blocking anti–CTLA-4 antibodies in melanoma and designed to shift the balance between immune stimulatory RCC patients suggest that this approach has a small therapeutic and inhibitory (regulatory) pathways will enhance therapeutic effect (47, 48).In one study, the addition of IL-2 to anti–CTLA- benefit. 4 antibody therapy in melanoma patients failed to show DCs are the most potent antigen-presenting cells and are additional clinical activity over IL-2 or anti–CTLA-4 antibody able to activate proinflammatory tumor-specific immune therapy alone, suggesting an overlap in the mechanisms of + pathways as well as disrupt regulatory pathways (13). action of these agents on CD4 Treg cells or the presence of Immature DCs sample and process antigens and then migrate other regulatory pathways (49). to T cell–rich areas in lymphoid organs (13, 34).In lymphoid To determine the presence of other regulatory cell popula- organs, mature DCs, which express costimulatory molecules, tions in cancer patients, we studied peripheral blood mono- present antigen and stimulate antigen-specific T cells to nuclear cells from healthy donors and advanced RCC patients in vivo proliferate.In the tumor-bearing host, DC maturation for the presence of Ts cells.T-cell subpopulations were and function seem inhibited (35–37).Treatment of tumor- identified by multicolor flow cytometry using anti-CD8, anti- bearing mice with an ex vivo generated DC vaccine reduces T- CD28, anti-CD4, and anti-CD25 antibodies (Coulter/Immu- cell tolerance and enhances antitumor immunity (24, 38). notech, Marseille, Cedex, France).Phenotypical differences in Although the optimal route of DC administration is not the proportion of T-cell subsets between healthy donors and defined, DC cross-priming of T lymphocytes requires cell-to- RCC patients were analyzed using an unpaired t test.T s cell cell contact, suggesting that direct administration of mature function was measured by a [3H]thymidine CD4+ T-cell DCs to lymph nodes would be advantageous.This is proliferation assay using irradiated KG-1 cells, which act as an supported by mouse studies that confirm enhanced protective antigen-presenting cell bridge (21). systemic immunity by intranodally administered DC-tumor Blood samples from 24 healthy donors and 29 RCC patients + À vaccines, as well as preliminary data in human studies using were
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