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1.
Cancer Res ; 73(12): 3591-603, 2013 Jun 15.
Article in English | MEDLINE | ID: mdl-23633484

ABSTRACT

Tumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation of CD8(+) T cells and Foxp3(+) Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8(+) T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8(+) tumor-infiltrating lymphocytes (TIL) expressed PD-1, whereas one third to half of CD8(+) TIL coexpressed PD-1 and CTLA-4. Double-positive (PD-1(+)CTLA-4(+)) CD8(+) TIL had characteristics of more severe dysfunction than single-positive (PD-1(+) or CTLA-4(+)) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8(+) TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8(+) and CD4(+) T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T-cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression.


Subject(s)
CTLA-4 Antigen/immunology , Cancer Vaccines/immunology , Neoplasms, Experimental/immunology , Programmed Cell Death 1 Receptor/immunology , T-Lymphocytes/immunology , Animals , Antibodies, Blocking/immunology , Antibodies, Blocking/pharmacology , B7-H1 Antigen/immunology , B7-H1 Antigen/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/metabolism , Cancer Vaccines/administration & dosage , Combined Modality Therapy , Cytokines/immunology , Cytokines/metabolism , Female , Flow Cytometry , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/transplantation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms, Experimental/pathology , Neoplasms, Experimental/therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Tumor Burden/immunology
2.
Oncoimmunology ; 2(1): e22059, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23483796

ABSTRACT

Adoptive T-cell transfer is among the most promising immunotherapies against cancer. To continue increasing the potential of this therapy, our studies focus on the inhibition of tumor recurrence. Recently, we have demonstrated several ways in which combination therapies involving multiple T-cell populations and immunostimulatory chemotherapy can enhance long-term survival.

3.
Cancer Res ; 72(18): 4753-64, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22836753

ABSTRACT

Oncolytic virotherapy offers the potential to treat tumors both as a single agent and in combination with traditional modalities such as chemotherapy and radiotherapy. Here we describe an effective, fully systemic treatment regimen, which combines virotherapy, acting essentially as an adjuvant immunotherapy, with adoptive cell transfer (ACT). The combination of ACT with systemic administration of a vesicular stomatitis virus (VSV) engineered to express the endogenous melanocyte antigen glycoprotein 100 (gp100) resulted in regression of established melanomas and generation of antitumor immunity. Tumor response was associated with in vivo T-cell persistence and activation as well as treatment-related vitiligo. However, in a proportion of treated mice, initial tumor regressions were followed by recurrences. Therapy was further enhanced by targeting an additional tumor antigen with the VSV-antigen + ACT combination strategy, leading to sustained response in 100% of mice. Together, our findings suggest that systemic virotherapy combined with antigen-expressing VSV could be used to support and enhance clinical immunotherapy protocols with adoptive T-cell transfer, which are already used in the clinic.


Subject(s)
Immunotherapy, Adoptive/methods , Melanoma, Experimental/therapy , Oncolytic Virotherapy/methods , T-Lymphocytes/transplantation , gp100 Melanoma Antigen/immunology , Adoptive Transfer , Animals , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Lymphocyte Activation/immunology , Melanoma, Experimental/immunology , Mice , Mice, Inbred C57BL , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/immunology , Vesicular stomatitis Indiana virus/immunology
4.
Hum Gene Ther ; 23(10): 1054-64, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22734672

ABSTRACT

An antitumor T-cell response can lead to tumor control without clearing all tumor cells. As long as residual tumor cells remain, there is a constant risk of escape from that T-cell response. We previously showed that adoptive transfer of anti-ova OT-I T cells into B16ova-bearing mice led to tumor regression followed by escape of tumors that had lost the ova gene, rendering the OT-I T cells ineffective. In this study, we hypothesized that simultaneous transfer of cytotoxic T lymphocytes targeted against two independent antigens would reduce selection for single-antigen-loss cells, thereby limiting tumor escape. Using OT-I and Pmel T cells to treat B16ova tumors, we found that early cotransfer could prevent tumor emergence in most mice, whereas neither T-cell specificity alone was able to do so. When combined with total body irradiation for the treatment of larger 7-day tumors, cotransfer was also better at limiting tumor recurrence, and the tumors that did escape combination therapy continued to express both target antigens. As adoptively transferred T cells also persisted in vivo, even in mice with recurrent tumors, we hypothesized that restimulation of these antitumor T cells would prolong survival of mice with recurrent tumors. Consistent with this hypothesis, administration of a low-dose regimen of cyclophosphamide following tumor escape slowed tumor growth in mice that had previously received T-cell therapy, but not in control-treated mice, an effect that was associated with increased activation of T cells in vitro by low- but not high-dose cyclophosphamide.


Subject(s)
Adoptive Transfer , Antigens, Neoplasm/immunology , T-Lymphocytes, Cytotoxic/immunology , Tumor Escape/immunology , Animals , Combined Modality Therapy , Cyclophosphamide/pharmacology , Cyclophosphamide/therapeutic use , Female , Melanoma, Experimental/immunology , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Mice, Transgenic , Ovalbumin/immunology , Receptors, Antigen, T-Cell/immunology , Survival Analysis , T-Lymphocytes, Cytotoxic/drug effects , Whole-Body Irradiation
5.
Int J Cancer ; 131(4): 844-54, 2012 Aug 15.
Article in English | MEDLINE | ID: mdl-21935923

ABSTRACT

Adoptive T cell therapy has been proven effective against melanoma in mice and humans. However, because most responses are incomplete or transient, cures remain rare. To maximize the efficacy of this therapy, it will be essential to gain a better understanding of the processes which result in tumor relapse. We studied these processes using B16ova murine melanoma and adoptive transfer of OT-I T cells. Transfer of T cells as a single therapy provided a significant survival benefit for mice with established subcutaneous tumors. However, tumors which initially regressed often recurred. By analyzing tumors which emerged in the presence of a potent OT-I response, we identified a novel tumor escape mechanism in which tumor cells evaded T cell pressure by undergoing major genomic changes involving loss of the gene encoding the target tumor antigen. Furthermore, we show that these in vivo processes can be recapitulated in vitro using T cell/tumor cell co-cultures. A single round of in vitro co-culture led to significant loss of the ova gene and a tumor cell population with rapidly induced and diverse karyotypic changes. Although these current studies focus on the model OVA antigen, the finding that T cells can directly promote genomic instability has important implications for the development of adoptive T cell therapies.


Subject(s)
Adoptive Transfer , Genomics , Melanoma, Experimental/immunology , T-Lymphocytes/cytology , Tumor Escape/genetics , Animals , Base Sequence , Coculture Techniques , DNA Primers , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Genomic Instability , In Situ Hybridization, Fluorescence , Lymphocyte Activation , Melanoma, Experimental/genetics , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Polymerase Chain Reaction , Real-Time Polymerase Chain Reaction , T-Lymphocytes/immunology
6.
Hum Gene Ther ; 22(11): 1343-53, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21366404

ABSTRACT

We have shown that the antitumor activity of vesicular stomatitis virus (VSV) against B16ova tumors in C57BL/6 mice is predominantly due to innate antiviral immune effectors. We have also shown that the innate immune-activating properties of VSV can be harnessed to prime adaptive T-cell responses against a tumor-associated antigen (TAA) if the virus is engineered to express the cDNA of the antigen. Here, we show that the combination of VSV expressing OVA as a model tumor antigen, along with adoptive T-cell therapy targeted against the same antigen, is superior to either treatment alone and induces systemic antitumor activity. In addition, we extend our findings with the OVA model to the therapeutic use of VSV expressing hgp100, a self TAA against which tolerance is well established in C57BL/6 mice. In contrast to VSV-ova, T-cell responses raised by VSV-hgp100 were insufficient to improve therapy against B16ova tumors compared with VSV-GFP alone. However, in combination with adoptive transfer of gp100-specific pmel T cells, intratumoral VSV-hgp100 cured significantly more mice than either virus or T cells alone. Even in an aggressive model of metastatic disease, antitumor therapy was generated at levels similar to those observed in the VSV-ova/OT-I model in which a potently immunogenic, nonself TAA was targeted. Therefore, individual poorly effective virotherapies and T-cell therapies that target self TAA of low immunogenicity, which reflects the situation in patients, can be combined to generate very effective antitumor therapy.


Subject(s)
Melanoma, Experimental/therapy , T-Lymphocytes/immunology , Vesicular stomatitis Indiana virus/physiology , gp100 Melanoma Antigen/immunology , Adoptive Transfer , Animals , Combined Modality Therapy , Immunity, Innate , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oncolytic Virotherapy , T-Lymphocytes/transplantation , Tumor Cells, Cultured , Vesicular stomatitis Indiana virus/immunology , Virus Replication , gp100 Melanoma Antigen/genetics
7.
Mol Ther ; 16(12): 1910-8, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18827807

ABSTRACT

To protect viral particles from neutralization, sequestration, nonspecific adhesion, and mislocalization following systemic delivery, we have previously exploited the natural tumor-homing properties of antigen-specific CD8+ T cells. Thus, OT-I T cells, preloaded in vitro with the oncolytic vesicular stomatitis virus (VSV), can deliver virus to established B16ova tumors to generate significantly better therapy than that achievable with OT-I T cells, or systemically delivered VSV, alone. Here, we demonstrate that preconditioning immune-competent mice with Treg depletion and interleukin-2 (IL-2), before adoptive T-cell therapy with OT-I T cells loaded with VSV, leads to further highly significant increases in antitumor therapy. Therapy was associated with antitumor immune memory, but with no detectable toxicities associated with IL-2, Treg depletion, or systemic dissemination of the oncolytic virus. Efficacy was contributed by multiple factors, including improved persistence of T cells; enhanced delivery of VSV to tumors; increased persistence of OT-I cells in vivo resulting from tumor oncolysis; and activation of NK cells, which acquire potent antitumor and proviral activities. By controlling the levels of virus loaded onto the OT-I cells, adoptive therapy was still effective in mice preimmune to the virus, indicating that therapy with virus-loaded T cells may be useful even in virus-immune patients. Taken together, our data show that it is possible to combine adoptive T-cell therapy, with biological therapy (Treg depletion+IL-2), and VSV virotherapy, to treat established tumors under conditions where none of the individual modalities alone is successful.


Subject(s)
Adaptation, Biological/immunology , Immunotherapy , Neoplasms/immunology , Neoplasms/therapy , Oncolytic Virotherapy , T-Lymphocytes/immunology , Animals , Antibodies/immunology , Antibodies/pharmacology , Antigens/immunology , Cell Line, Tumor , Immunologic Memory/immunology , Interleukin-2/immunology , Killer Cells, Natural/immunology , Mice , Neoplasms/genetics , T-Lymphocytes/drug effects , Vesiculovirus/genetics
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