Checkpoint blockade in combination with cancer vaccines
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.
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Combination of CTLA-4 blockade with MUC1 mRNA nanovaccine induces enhanced anti-tumor CTL activity by modulating tumor microenvironment of triple negative breast cancer
2022, Translational OncologyCitation Excerpt :Combinations of immune checkpoint blockade with targeting other immune checkpoints is moving forward in TNBC [15]. Preclinical and clinical data supports the use of cancer vaccines with anti-CTLA-4 antibody [16]. Tumor-targeted radiotherapy (RT) is used to generate an in situ tumor vaccine [17].
Targeted co-delivery of Trp-2 polypeptide and monophosphoryl lipid A by pH-sensitive poly (β-amino ester) nano-vaccines for melanoma
2019, Nanomedicine: Nanotechnology, Biology, and MedicineCitation Excerpt :Meanwhile, the median survival time of combination group was 1.2-fold higher than T/M@mPS and 1.6-fold higher than DPPA-1 along. We speculate that non-response to immune checkpoint inhibitors resulting from the lack of specific effector cells towards tumor might benefit from the specific immune stimulation through vaccine.48,58,59 Another major concern is safety.
Nanotechnology is an important strategy for combinational innovative chemo-immunotherapies against colorectal cancer
2019, Journal of Controlled ReleaseCitation Excerpt :Besides the approval of the ipilimumab (Yervoy®) and nivolumab (Opdivo®) combination for the treatment of MSI-H or dMMR mCRC patients previously treated with standard chemotherapeutic drugs, broader combinations of multiple immune modulators are also under evaluation. Some immune effectors enhance tumor killing by stimulating T cells with greater and specific cytolytic activity, while others are designed to interfere with immunomodulatory or immunosuppressive mechanisms [233]. Table 9 summarizes several preclinical and clinical studies involving different combinatorial immunotherapeutic strategies for CRC treatment.
PD-1/PD-L1 checkpoint blockades in non-small cell lung cancer: New development and challenges
2017, Cancer LettersCitation Excerpt :Inhibition of gamma isoform of phosphoinositide 3-kinase (PI3K-γ, highly expressed in immune-suppressive myeloid cells) by IPI-549 (PI3K-γ inhibitor) restored sensitivity to checkpoint blockades and inhibited tumor growth in mouse models [67]. Animal models demonstrated that significant tumor regression was observed when the vaccine combined with concurrently administered anti-PD-1 antibody [68,69]. Besides the above combinations, there are also other preliminary data that tried to enhance the efficacy or overcome the resistance of PD-1/PD-L1 blockades from different mechanism.
Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy
2017, Advanced Drug Delivery ReviewsCitation Excerpt :Accordingly, biomarkers are in development to identify individuals most likely to benefit from checkpoint blockade [3,4]. Furthermore, considerable preclinical and clinical research focuses on how the efficacy of checkpoint inhibition may be improved when used in combination with agents with orthogonal but synergistic signaling activity, for example targeted therapies [5,6] and cancer vaccines [7], which expand the population of tumor antigen-specific lymphocytes. Significant immune-related adverse events (iRAE) and toxicities associated with treatment with checkpoint inhibitors when used alone or in combination (e.g. vemurafenib and ipimumab [8]) also remain to be minimized [9–11].