Interest of Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine

Galaine, Jeanne; Borg, Christophe; Godet, Yann; Adotévi, Olivier

doi:10.3390/vaccines3030490

Cited by 43 publications

(29 citation statements)

References 102 publications

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“…3 Lessons learnt from previous clinical trials support that future anticancer vaccines should take into account some critical points such as the ability of vaccine to stimulate high quality memory antitumor CD8 T-cell responses, to induce CD4 helper T-cell response and to block immune suppression and/or exhaustion. 4,5,40,41 In our study, we reported the ability of the mTOR inhibitor temsirolimus to highly potentiate anticancer vaccines when combined with T regs blockade in vivo. This effect is mainly driven by the induction of antitumor memory CD8 T cells.…”

Section: Discussionmentioning

confidence: 81%

Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy

Beziaud

Boullerot

Tran

et al. 2018

Intl Journal of Cancer

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mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor-specific CD8 T-cell responses induced by vaccination. Furthermore, tumor-specific CD8 T cells induced by the bi-therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127 CD62L ) CD8 T cells compared to vaccination alone. We demonstrated that regulatory CD4 T cells (T ) expansion in vivo limits the efficacy of the bi-therapy by altering the antitumor CD8 T-cell responses. Finally, the use of a small molecule CCR4 antagonist to prevent T induction considerably improved the efficacy of the bi-therapy by enhancing CD8 T cells-mediated antitumor immunity. Taken together, our study highlights the potential interest of combining cancer vaccines with drugs that promote memory CD8 T cells and inhibit T .

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Section: Discussionmentioning

confidence: 81%

Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy

Beziaud

Boullerot

Tran

et al. 2018

Intl Journal of Cancer

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“…We describe that moDCs stimulated by tumor supernatant of the highly cytotoxic NB-PDT condition are able to provide the adequate stimulatory signals for the proliferation of CD4+ T cells (Figure 6a) and differentiation towards Th1 CD4+ effector T cells, as indicated by the substantial release of IFNγ (Figure 6b). Th1 CD4+ effector T cells are known to have a clear antitumor role and, via IFNγ release, can sustain a potent cellular immune response involving CD8+ cytotoxic T cells [40,41]. Although the activation of these cytotoxic T cells was not investigated in our study, their importance for tumor control is evident and we will further expand on this aspect in future in vivo studies.…”

Section: Discussionmentioning

confidence: 92%

The Potential of Nanobody-Targeted Photodynamic Therapy to Trigger Immune Responses

Hernández

Angelier

D’Ondes

et al. 2020

Cancers

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M.L.A.); a.dimaggio@students.uu.nl (A.D.M.); Y.Yu@uu.nl (Y.Y.)Abstract: Nanobody-targeted photodynamic therapy (NB-PDT) has been recently developed as a more tumor-selective approach rather than conventional photodynamic therapy (PDT). NB-PDT uses nanobodies that bind to tumor cells with high affinity, to selectively deliver a photosensitizer, i.e., a chemical which becomes cytotoxic when excited with light of a particular wavelength. Conventional PDT has been reported to be able to induce immunogenic cell death, characterized by the exposure/release of damage-associated molecular patterns (DAMPs) from dying cells, which can lead to antitumor immunity. We explored this aspect in the context of NB-PDT, targeting the epidermal growth factor receptor (EGFR), using high and moderate EGFR-expressing cells. Here we report that, after NB-PDT, the cytoplasmic DAMP HSP70 was detected on the cell membrane of tumor cells and the nuclear DAMP HMGB1 was found in the cell cytoplasm. Furthermore, it was shown that NB-PDT induced the release of the DAMPs HSP70 and ATP, as well as the pro-inflammatory cytokines IL-1β and IL-6. Conditioned medium from high EGFR-expressing tumor cells treated with NB-PDT led to the maturation of human dendritic cells, as indicated by the upregulation of CD86 and MHC II on their cell surface, and the increased release of IL-12p40 and IL-1β. Subsequently, these dendritic cells induced CD4+ T cell proliferation, accompanied by IFNγ release. Altogether, the initial steps reported here point towards the potential of NB-PDT to stimulate the immune system, thus giving this selective-local therapy a systemic reach.Despite being a selective and controllable treatment against tumor cells, therapies known to be considerably aggressive towards all tissues (i.e., chemo-and radiotherapy) are still the mainstream clinical practice, when it comes to combat cancer [5]. Some current barriers for the establishment of PDT in routine practice are the required technology, complex dosimetry, limited tissue penetration of light and/or PS, lack of tumor specificity and prolonged skin photosensitivity [1,5]. Efforts have been put into improving the selectivity of PDT towards the cancer cells by using antibodies, an approach which is now in phase II clinical trial (NCT02422979) [6]. Conjugation of a water-soluble PS (IRDye700DX) to an antibody allows the PS to be specifically delivered to cancer cells overexpressing a certain antigen on the cell membrane. In this manner, two levels of specificity are established: the delivery of PS to target-expressing cells and the local application of light at the tumor site.Another strategy to render PDT more tumor-selective is nanobody-targeted PDT (NB-PDT), which also utilizes the near-infrared PS IRDye700DX. In this case, however, a nanobody is used to provide the first level of specificity [7,8]. NBs are the smallest binding domains found in nature (~15 kDa) and consist uniquely of the variable domain of heavy chain antibodies present in Camelids [9]. The use of a NB for PDT brings a ...

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“…This correlates with studies where engagement of the T-helper compartment has been shown to increase the efficacy of cancer vaccine strategies. [32][33] Aarntzen and colleagues have demonstrated that combining CD4 and CD8 epitopes improves median progression-free survival of patients with stage III and IV melanoma with detectable antigen-specific responses among skin-infiltrating lymphocytes. 34 Similar approaches featured the production of longer peptides including both CD4 and CD8 epitopes.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic vaccines increase the response to PD-L1 blockade in immunogenic and poorly immunogenic tumors

et al. 2018

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Activation of immune checkpoint pathways and limited T- cell infiltration result in immunological escape of tumors. Although immune checkpoint inhibitors are currently approved for several types of cancers, the response rate is often limited by the lack of tumor specific T-cells within the malignant tissue. Therefore, new combinatorial strategies are needed to enhance the clinical benefit of immune checkpoint inhibitors. We have previously developed PeptiCRAd, an oncolytic vaccine platform capable of directing the immune response toward tumor epitopes. In this study, we evaluated whether the platform could be used to increase the response rate to checkpoint inhibitors in both highly immunogenic and poorly immunogenic tumors, such as melanoma and triple negative breast cancer (TNBC). We report here that anti-PD-L1 therapy in combination with PeptiCRAd significantly reduced the growth of melanomas and increased the response rate to checkpoint inhibition. In fact, we registered a higher rate of complete responses among mice treated with the combination. This approach promoted the presence of non-exhausted antigen-specific T-cells within the tumor in comparison to anti-PD-L1 monotherapy. Furthermore, we found that targeting both MHC-I and II restricted tumor epitopes was necessary to decrease the growth of the poorly immunogenic TNBC model 4T1 and that combination with PD-L1 blockade increased the number of responders to checkpoint inhibition. Finally, the described strategy was validated in a translational model using HLA matched human PBMCs and tumor cell lines. Consistent to our previous results, improved cytotoxicity was observed with combination of PeptiCRAd and anti-PD-L1. These results demonstrate that oncolytic virus based cancer vaccine can significantly improve the response rate to checkpoint blocking antibodies in the context of immunogenic and non-immunogenic tumors.

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Interest of Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine

Cited by 43 publications

References 102 publications

Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy

Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy

The Potential of Nanobody-Targeted Photodynamic Therapy to Trigger Immune Responses

Oncolytic vaccines increase the response to PD-L1 blockade in immunogenic and poorly immunogenic tumors

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