Elsevier

Vaccine

Volume 33, Issue 51, 16 December 2015, Pages 7377-7385
Vaccine

Checkpoint blockade in combination with cancer vaccines

https://doi.org/10.1016/j.vaccine.2015.10.057Get rights and content

Abstract

Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study.

Section snippets

Rationale for combination of cancer vaccines and checkpoint blockade

Although there has been a longstanding interest in harnessing the immune system to destroy tumors, the discoveries of unique or overexpressed antigens on tumors that could be recognized by T cells and antibodies as targets for immune attack and of antigen-presenting cells such as dendritic cells that are required for stimulation of the tumor antigen-specific T cells dramatically accelerated the development of immunotherapies for malignancies. The ever growing list of tumor antigens and delivery

Combinations of anti-CTLA-4 antibody plus vaccines

Early studies demonstrated a consistently greater anti-tumor effect for combinations of anti-CTLA-4 antibody and vaccines compared with either alone in murine models [21], [36], [37], [38]. For example, in the rapidly growing B16-BL6 melanoma model, although administration of anti-CTLA-4 antibody (hamster IgG mAb clone 9H10) alone had no effect, and a vaccine based on irradiated GM-CSF-producing B16-BL6 cells only delayed growth, the combination of the vaccine and anti-CTLA-4 Ab blockade caused

Anti-CTLA-4 antibody plus vaccines in human studies

Consistent with murine experiments, human studies with anti-CTLA-4 antibody have generally demonstrated an increased frequency of effector T cells in circulation [13], [51], [52] or an increased ratio of effector cells to Treg in tumor tissue [52] although one study has demonstrated a decrease in FOXP3+ Treg in tumor [52]. No changes in Treg suppressive function have been observed with anti-CTLA-4 therapy. Other cell types such as Th17 cells [53] may be impacted as well. Despite the increase in

Anti-PD-1 plus vaccines

As described above, a challenge to the application of cancer vaccines has been the concern that despite activation of antigen-specific T cell responses, the tumor environment dampens effector T cell function [63]. Further, the repertoire of clonally expanded tumor antigen-reactive cells within TILs, whether spontaneously responding or activated by vaccines [25], expresses PD-1 [64] and as such, may be targeted for exhaustion. Vaccines have been reported to induce, coincident with intratumoral

Clinical data for anti-PD-1 plus vaccines

Clinical data for combinations of anti-PD-1 therapy and vaccines is limited. Weber and colleagues [74] treated patients with unresectable stage III and IV melanoma in cohorts that received doses of nivolumab 3 mg/kg without vaccine and nivolumab 1,3, and 10 mg/kg with peptide vaccine (consisting of gp100209–217 (210M), MART-126–35 (27L), gp100280–288 (288V) and NY-ESO-1157–165 (165V) peptides emulsified in Montanide ISA 51 VG). Two cycles of six doses of nivolumab and peptide vaccine administered

Other checkpoint blockade and vaccine combinations

As described above, CTLA-4 and PD-1 are thought to have their predominant effect at different phases of the immune cycle with some overlap, but they also act on T cell populations of different avidities. Recent analyses of genomic and functional signatures from T cells exposed to checkpoint blockade have demonstrated that CTLA-4 blockade induces a “proliferative signature” predominantly in a subset of memory T cells [76]. In contrast, PD-1 blockade modulates cytolytic functions, and their

Combining checkpoint blockade, Treg depletion, and vaccines

Because Treg may persist despite checkpoint blockade, some studies have studied Treg depletion prior to vaccination in conjunction with checkpoint blockade. Cyclophosphamide, because of its widely accepted role at low doses in enhancing anti-tumor immunity by reducing the number and function of Treg cells [69], [80], [81] has typically been used. Even for combination vaccine plus anti-PD-1 antibody CT-011, the addition of cyclophosphamide could overcome residual Treg-mediated suppression

Combined checkpoint blockade and other immune modulators with vaccines

Because ligation of CD40 on dendritic cells increases their maturation level and T cell stimulatory function, a booster vaccination plus combination treatment with agonistic anti-CD40 and anti-CTLA-4 monoclonal antibodies was tested and found to generate the greatest anti-tumor activity associated with significantly prolonged tumor-specific CD8 T cell response in spleens of the mice receiving the combination treatment [83].

4-1BB (CD137), another T cell costimulatory receptor in the TNFR

Other considerations for vaccine plus checkpoint blockade

Although we have discussed the role of checkpoint blockade in enhancing vaccine efficacy with limited consideration of the features of the coadministered vaccine, there may be greater necessity for certain checkpoints depending on the vaccine used, its mechanism of action, and its effects at the injection site or tumor. Early preclinical studies reported that CTLA-4 blockade synergized with a GM-CSF-expressing but not a B7-expressing vaccine [21]. Because GM-CSF-expressing vaccines cause

Summary

Preclinical data supports the combination of cancer vaccines and checkpoint blockade, each enhancing the efficacy of the other. Anti-CTLA4 antibodies, whether by reducing inhibitory signaling in activated T cells or interfering with Treg, cause an increase in intratumoral effector T cells, favorably altering the intratumoral balance of effector T cells and Treg. Anti-CTLA-4 therapy increases and maintains the vaccine-induced stimulation of CD8+ effectors and their trafficking to tumors.

Future directions

Already the question of what causes resistance to PD-1 blockade has led to the observation that expression of other inhibitory receptors persists in anti-PD-1 antibody treated tumors. Sawada [28] studied the expression of PD-1, CTLA-4, and LAG-3 on peptide-specific CTLs at the tumor site following intratumoral immunization with OVA peptide combined with αPD-1 Ab. The expression of PD-1 and CTLA-4 was decreased but LAG-3 was not, suggesting the future need to target other inhibitory receptors.

Conflicts of interest

Dr. Michael Morse has received research grant support from Bristol Meier Squibb and Merck.

References (97)

  • B. Li et al.

    Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb

    Clin Immunol

    (2007)
  • M.D. Vu et al.

    OX40 costimulation turns off Foxp3+ Tregs

    Blood.

    (2007)
  • M. Tagliamonte et al.

    Antigen-specific vaccines for cancer treatment

    Hum Vaccin Immunother

    (2014)
  • S.P. Patel et al.

    Designing effective vaccines for colorectal cancer

    Immunotherapy

    (2014)
  • P.W. Kantoff et al.

    Sipuleucel-T immunotherapy for castration-resistant prostate cancer

    N Engl J Med

    (2010)
  • P.W. Kantoff et al.

    Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer

    J Clin Oncol

    (2010)
  • G. Kroemer et al.

    Victories and deceptions in tumor immunology: Stimuvax(®)

    Oncoimmunology

    (2013)
  • N.A. Sheikh et al.

    Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer

    Cancer Immunol Immunother

    (2013)
  • S. Walter et al.

    Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

    Nat Med

    (2012)
  • S.A. Funt et al.

    Ctla-4 antibodies: new directions, new combinations

    Oncology (Williston Park)

    (2014)
  • K.S. Peggs et al.

    Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies

    J Exp Med

    (2009)
  • T. Takahashi et al.

    Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4

    J Exp Med

    (2000)
  • S. Read et al.

    Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation

    J Exp Med

    (2000)
  • D. O’Mahony et al.

    A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy

    Clin Cancer Res

    (2007)
  • C.I. Liakou et al.

    CTLA-4 blockade increases IFNgamma-producing CD4+ ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients

    Proc Natl Acad Sci U S A

    (2008)
  • T.R. Simpson et al.

    Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma

    J Exp Med

    (2013)
  • M.J. Selby et al.

    Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells

    Cancer Immunol Res

    (2013)
  • K. Wing et al.

    CTLA-4 control over Foxp3+ regulatory T cell function

    Science

    (2008)
  • D. Leach et al.

    Enhancement of antitumor immunity by CTLA-4 blockade

    Science

    (1996)
  • E.D. Kwon et al.

    Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer

    Proc Natl Acad Sci USA

    (1997)
  • A.A. Hurwitz et al.

    CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma

    Proc Natl Acad Sci U S A

    (1998)
  • K.E. Pauken et al.

    Overcoming T cell exhaustion in infection and cancer

    Trends Immunol

    (2015)
  • R.H. Thompson et al.

    PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma

    Clin Cancer Res

    (2007)
  • S.R. Sierro et al.

    Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity

    Eur J Immunol

    (2011)
  • M.A. Postow et al.

    Immune checkpoint blockade in cancer therapy

    J Clin Oncol

    (2015)
  • J.M. Taube Taube et al.

    Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape

    Sci Transl Med

    (2012)
  • Y. Sawada

    Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes

    Int J Oncol

    (2015)
  • P.C. Tumeh et al.

    PD-1 blockade induces responses by inhibiting adaptive immune resistance

    Nature

    (2014)
  • J. Fourcade et al.

    PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8+ T cells induced by melanoma vaccines

    Cancer Res

    (2014)
  • R.M. Wong et al.

    Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs

    Int Immunol

    (2007)
  • C.A. Chambers et al.

    CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy

    Annu Rev Immunol

    (2001)
  • Y. Latchman et al.

    PD-L2 is a second ligand for PD-1 and inhibits T cell activation

    Nat Immunol

    (2001)
  • J.A. Brown et al.

    Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production

    J Immunol

    (2003)
  • A. van Elsas et al.

    Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation

    J Exp Med

    (1999)
  • A.A. Hurwitz et al.

    Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade

    Cancer Res

    (2000)
  • E.L. Williams et al.

    Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model

    Clin Cancer Res

    (2013)
  • L.I. Dos Santos et al.

    Blockade of CTLA-4 promotes the development of effector CD8(+) T lymphocytes and the therapeutic effect of vaccination with an attenuated protozoan expressing NY-ESO-1

    Cancer Immunol Immunother

    (2015)
  • S.A. Quezada et al.

    CTLA-4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells

    J Clin Invest

    (2006)
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