Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients

Rodríguez-Ruiz, María E.; Perez-Gracia, José Luis; Rodríguez, Inmaculada; Alfaro, Carlos; Oñate, Carmen; Pérez, Guiomar; Gil-Bazo, Ignacio; Benito, Alberto; Inogés, Susana; Cerio, Ascensión López‐Díaz de; Ponz-Sarvisé, Mariano; Resano, L.; Berraondo, Pedro; Barbés, Benigno; Martín‐Algarra, Salvador; Gúrpide, Alfonso; Sanmamed, Miguel F.; Andrea, Carlos de; Salazar, Andrés M.; Melero, Ignacio

doi:10.1093/annonc/mdy089

Cited by 118 publications

(94 citation statements)

References 34 publications

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“…Published previous experience using TGFb blockade with mAbs in monotherapy showed improved local tumor control of radiotherapy without abscopal effects (33). We have observed that TGFb blockade achieves abscopal effects beyond the previously reported spectacular effects reached by unilateral radiotherapy plus anti-PD-1 plus anti-CD137 mAbs in combination (3,18). In our hands, the quadruple combination approach achieves abscopal effects against large and well-established transplanted tumors.…”

Section: Discussionsupporting

confidence: 52%

“…The role of radiotherapy as a means to augment response to immunotherapy has been explored in preclinical models (1,2) and is currently being studied in multiple clinical trials (3)(4)(5)(6)(7). The most interesting experiments are those in which radiation elicits efficacy outside the irradiation fields, the so-called abscopal effects of radiotherapy (1,8).…”

Section: Introductionmentioning

confidence: 99%

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TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies

Rodríguez-Ruiz

Rodríguez

Mayorga

et al. 2019

Molecular Cancer Therapeutics

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Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGFb expression or activation increases in irradiated tissues, we tested whether TGFb blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Indeed, TGFb blockade with 1D11, a TGFb-neutralizing mAb, markedly enhanced abscopal effects and overall treatment efficacy against subcutaneous tumors of either 4T1 breast cancer cells or large MC38 colorectal tumors. Increases in CD8 T cells infiltrating the nonirradiated lesion were documented upon combined treatment, which intensely expressed Granzyme-B as an indicator of cytotoxic effector capability. Interestingly, tumor tissue but not healthy tissue irradiation results in the presence of higher concentrations of TGFb in the nonirradiated contralateral tumor that showed smad2/3 phosphorylation increases in infiltrating CD8 T cells. In conclusion, radiotherapy-induced TGFb hampers abscopal efficacy even upon combination with a potent immunotherapy regimen. Therefore, TGFb blockade in combination with radioimmunotherapy results in greater efficacy.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies

Rodríguez-Ruiz

Rodríguez

Mayorga

et al. 2019

Molecular Cancer Therapeutics

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“…Different TLR agonists have been tested in experimental mouse tumors models [22][23][24][25] and are being investigated in early clinical trials to assess their safety and efficacy in cancer patients, most frequently in combination with conventional or target therapies [26][27][28]. Here, we have studied the TLR7 agonist Imiquimod (IMQ), one of the few approved by FDA for the treatment of nonmelanoma skin cancers [26,29], and the TLR3 agonist Poly(I:C), a dsRNA analog under study in the clinic as adjuvant in antitumor vaccines [27,[30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Poly(I:C) stimulation is superior than Imiquimod to induce the antitumoral functional profile of tumor‐conditioned macrophages

et al. 2019

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Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor‐Associated Macrophages (TAMs) acquire an immune‐suppressive and tumor‐promoting phenotype. With the aim to re‐educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor‐Conditioned Macrophages (TC‐Mϕ) differentiated in the presence of tumor cell supernatants. Our results show that TC‐Mϕ respond differently from conventional M2‐polarized macrophages. Upon stimulation with IMQ, TC‐Mϕ did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC‐Mϕ produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL‐1β and IL‐6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC‐Mϕ against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC‐Mϕ is superior than IMQ in terms of macrophage re‐education toward antitumor effectors.

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“…This case demonstrates the role of radiations in ensuring the release of disruptions to the blood-brain barrier and tumorassociated antigens [12]. AbEs are mainly sporadic events of tumors that begin to grow following RT treatments as observed through irradiated sites from a distance [13]. Mechanisms often have several origins, including infection by inflammatory agents such as cytokines, the distance effects, and the secondary immunity to devices [14].…”

Section: Abscopal Effects -Current and Future Practicesmentioning

confidence: 91%

Radiation Therapy as a Modality to Create Abscopal Effects: Current and Future Practices

Adjepong

Malik

2020

Cureus

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In our empathetic understanding of abscopal effect (AbE), research has shown that the immune system is stimulated by radiation, which results in the formation of an AbE. The AbE is referred to as a response from the irradiated volume. Despite the existence of key gaps in our understanding, there is an urgent need to explore what the underlying effect is. The aim of this article is to argue neurosurgeons and the healthcare practitioner's knowledge of the AbE. Our goal is to identify more gaps in our understanding of the AbE and seal other gaps as well. This study will review medical journals and bring together the most updated information related to AbEs.

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Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients

Abstract: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Cited by 118 publications

References 34 publications

TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies

TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies

Poly(I:C) stimulation is superior than Imiquimod to induce the antitumoral functional profile of tumor‐conditioned macrophages

Radiation Therapy as a Modality to Create Abscopal Effects: Current and Future Practices

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