Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors

Karaki, Soumaya; Anson, Marie; Tran, Thi; Giusti, Delphine; Blanc, Charlotte; Oudard, Stéphane; Tartour, Éric

doi:10.3390/vaccines4040037

Cited by 53 publications

(36 citation statements)

References 147 publications

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“…32 Various cancer vaccines combined with inhibitory pathway blockade have been validated in preclinical models, and enhanced T cell infiltration of various tumors has been demonstrated following this combination therapy. 50…”

Section: Discussionmentioning

confidence: 99%

Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer

et al. 2018

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Triple negative breast cancer (TNBC), which constitutes 10%-20% of all breast cancers, is associated with aggressive progression, a high rate of metastasis, and poor prognosis. The treatment of patients with TNBC remains a great clinical challenge. Preclinical reports support the combination immunotherapy of cancer vaccines and immune checkpoint blockades in non-immunogenic tumors. In this study, we constructed nanoparticles (NPs) to deliver an mRNA vaccine encoding tumor antigen MUC1 to dendritic cells (DCs) in lymph nodes to activate and expand tumor-specific T cells. An anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) monoclonal antibody was combined with the mRNA vaccine to enhance the anti-tumor benefits. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen-specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone. These data support both the NP as a carrier for delivery of mRNA vaccine and a potential combination immunotherapy of the NP-based mRNA vaccine and the CTLA-4 inhibitor for TNBC.

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Section: Discussionmentioning

confidence: 99%

Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer

et al. 2018

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“…In this context, several preclinical and clinical studies demonstrated synergistic effect of combinatorial blockade of two or more immune checkpoint molecules . Nevertheless, although checkpoint inhibitors are considered a revolution in the immunotherapy of cancer, depending on the tumor type, the majority of patients remain resistant to this therapy or relapse over time . Thus, as previously observed for cancer vaccines, only targeting one side of the balance will not be sufficient and therefore alleviating inhibition by checkpoint inhibitors will need to be combined with stimulating the immune system, using anticancer vaccines …”

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confidence: 99%

Immune checkpoint blockade combined with IL‐6 and TGF‐β inhibition improves the therapeutic outcome of mRNA‐based immunotherapy

Bialkowski

Jeught

Bevers³

et al. 2018

Intl Journal of Cancer

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Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T-cell exhaustion or disrupt the cross-talk between cancer stem cells and the tumor-promoting microenvironment. Here, we demonstrate that a three-arm combination therapy-consisting of an mRNA-based vaccine to induce antigen-specific T-cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD-1, TIM-3, LAG-3), and antibodies targeting IL-6 and TGF-β-improves the therapeutic outcome in subcutaneous TC-1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor-specific immunity and simultaneously targeting multiple resistance mechanisms.

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“…Numerous preclinical and clinical studies are ongoing and planned concerning the use of these checkpoint inhibitor antibodies in combination with other forms of therapy, including other immunotherapeutics. [12][13][14][15][16] Avelumab and atezolizumab are unique among currently employed anti-PD-L1 MAbs in that they are fully human immunoglobulin IgG1s with a non-mutated Fc, which also renders them capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). 17,18 Several other MAbs currently employed in cancer therapy are also of the IgG1 isotype, including cetuximab, trastuzumab, and rituximab.…”

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confidence: 99%

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

et al. 2017

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NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety profile. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti–PD-L1 monoclonal antibody, which has shown evidence of clinical activity in a range of human tumors. Prior in vitro studies have shown that avelumab has the ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells when combined with NK cells. In the studies reported here, the ability of avelumab to enhance the lysis of a range of human carcinoma cells by irradiated haNK cells via the ADCC mechanism is demonstrated; this ADCC is shown to be inhibited by anti-CD16 blocking antibody and by concanamycin A, indicating the use of the granzyme/perforin pathway in tumor cell lysis. Studies also show that while NK cells have the ability to lyse aNK or haNK cells, the addition of NK cells to irradiated haNK cells does not inhibit haNK-mediated lysis of human tumor cells, with or without the addition of avelumab. Avelumab-mediated lysis of tumor cells by irradiated haNK cells is also shown to be similar to that of NK cells bearing the V/V Fc receptor high affinity allele. These studies thus provide the rationale for the clinical evaluation of the combined use of avelumab with that of irradiated adoptively transferred haNK cells.

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Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors

Cited by 53 publications

References 147 publications

Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer

Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer

Immune checkpoint blockade combined with IL‐6 and TGF‐β inhibition improves the therapeutic outcome of mRNA‐based immunotherapy

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

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