Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

Pol, Jonathan; Lévesque, Sophie; Workenhe, Samuel T.; Gujar, Shashi; Bœuf, Fabrice Le; Clements, Derek R.; Fahrner, Jean-Eudes; Fend, Laetitia; Bell, John C.; Mossman, Karen; Fučíková, Jitka; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

doi:10.1080/2162402x.2018.1503032

Cited by 70 publications

(56 citation statements)

References 368 publications

(541 reference statements)

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“…adoptive T cell therapies, cancer vaccines). [53][54][55][56][57][58][59] Notwithstanding the aforementioned limitations, our results delineate a strategy for tumor treatment that involves a therapy consisting in the administration of three drug classes: (i) ICD inducers exemplified by MTX and OXA, (ii) CRMs exemplified by HC and Spd and substitutable for fasting (if the nutritional status of the patient allows it) and (iii) ICIs targeting the PD-1/PD-L1 interaction. As shown here, such a triple combination has the potential to cure the majority of mice bearing established fibrosarcomas.…”

Section: Discussionmentioning

confidence: 91%

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice

et al. 2019

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We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8 + T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumorbearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 91%

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice

et al. 2019

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“…During the treatment and observation period, tumors in the mock group exhibited central necrosis or cavitation when the size increased to 600-1,000 mm 3 . Tumors in the oHSV2 treatment group exhibited necrosis in the early stages of treatment at a size of 100-200 mm 3 , and a local black scab and tumor regression appeared. On day 13 after the first treatment, one mouse in the oHSV2 treatment group exhibited tumor regression.…”

Section: Ohsv2 Treatment Inhibits Tumor Growth and Prolongs Survivalmentioning

confidence: 97%

“…For the past few years, the emergence of virotherapy and in-depth research into it has shed new light on the treatment of solid tumors. 3 Oncolytic viruses (OVs) have attracted much attention because of their unique characteristics.…”

Section: Introductionmentioning

confidence: 99%

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

Zhang

Liang

et al. 2020

Molecular Therapy - Oncolytics

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Oncolytic viruses are promising immunoreagents. Numerous studies have shown that oncolytic virotherapy is effective for many tumors. Herein, we investigated the therapeutic effect of oHSV2, an oncolytic type 2 herpes simplex virus, on mouse colon carcinoma. The in vivo antitumor efficacy of oHSV2 was observed in both unilateral and bilateral colon cancer models. oHSV2 effectively eliminated tumors and prolonged the survival of mice without side effects. Additionally, treatment with oHSV2 effectively prevented the growth of rechallenged tumors and distant implanted tumors. The specific killing ability of splenic immune cells to tumor cells was enhanced. oHSV2 treatment effectively reduced the content of inhibitory immune cells (regulatory T cells [Tregs] and myeloid-derived suppressor cells [MDSCs]) and increased the content of positive immune cells (natural killer [NK], CD8 + T, and dendritic cells [DCs]) in the spleen. Moreover, treatment with oHSV2 remodeled the tumor immune microenvironment. In summary, treatment with oHSV2 can effectively eliminate primary tumors, generate tumor-specific immunity, and elicit immune memory to inhibit tumor recurrence and metastasis. Furthermore, this virotherapy can reshape the immune status of the spleen and tumor microenvironment in mice, which can further improve the therapeutic antitumor effect.

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“…By releasing tumor antigens in concert with DAMPs (danger-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns) during viral infection, oncolytic virotherapy acts as an antigen-agnostic in situ tumor vaccine [12]. While the herpes virus talimogene laherparepvec has been approved by the FDA and EMA, several other oncolytic viruses are currently in clinical trials, including vaccinia, adeno-, rhabdo-and reoviruses [13]. Oncolytic measles vaccines are under clinical investigation for treatment of several tumor entities, and early trials have indicated the safety and efficacy of this approach [12].…”

Section: Introductionmentioning

confidence: 99%

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

Busch

Kubon

Mayer

et al. 2020

Viruses

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Priming and activation of CD8 + T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics systems allow for insertion of additional genes, including heterologous antigens. Here, we designed recombinant measles vaccine vectors for priming and activation of antigen-specific CD8 + T cells. For proof-of-concept, we used cytotoxic T lymphocyte (CTL) lines specific for the melanoma-associated differentiation antigen tyrosinase-related protein-2 (TRP-2), or the model antigen chicken ovalbumin (OVA), respectively. We generated recombinant measles vaccine vectors with TRP-2 and OVA epitope cassette variants for expression of the full-length antigen or the respective immunodominant CD8 + epitope, with additional variants mediating secretion or proteasomal degradation of the epitope. We show that these recombinant measles virus vectors mediate varying levels of MHC class I (MHC-I)-restricted epitope presentation, leading to activation of cognate CTLs, as indicated by secretion of interferon-gamma (IFNγ) in vitro. Importantly, the recombinant OVA vaccines also mediate priming of naïve OT-I CD8 + T cells by dendritic cells. While all vaccine variants can prime and activate cognate T cells, IFNγ release was enhanced using a secreted epitope variant and a variant with epitope strings targeted to the proteasome. The principles presented in this study will facilitate the design of recombinant vaccines to elicit CD8 + responses against pathogens and tumor antigens.

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Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

Cited by 70 publications

References 368 publications

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

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