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      On target methods to induce abscopal phenomenon for Off‐Target effects: From happenstance to happenings

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          Abstract

          Although the “abscopal phenomenon” has been described several decades ago, this phenomenon lately has been obtaining momentous traction with the dawn of immune‐based therapies. There has been increased cross talk among radiation oncologists, oncologists and immunologists and consequently a surge in the number of prospective clinical trials. This must be coupled with translation work from these clinical trials to aid in eventual identification of patients who may benefit. Abscopal effects may be induced by local and systemic methods, conventional radiotherapy, particle radiation, radionucleotide methods, cryoablation and brachytherapy. These approaches have all been reported to be stimulate abscopal effect. Immune induction by immune checkpoint therapy, immune adjuvants, cellular therapy including CAR and NK cell therapies may generate systemic abscopal response. With increasing recognition of this effect, there remains a lot of work to explore the modalities of inducing abscopal responses and ultimate prediction or prognostication on stratifying who may benefit. Ultimately, there is an urgent need for prospective studies and data to tease apart which one of these modalities can be applied to the appropriate candidate, to the appropriate cancer at the appropriate setting. This review seeks to elucidate readers on the different modalities of radiation, systemic therapies and other techniques rarely explored to potentiate the abscopal effect from a mere coincidence to a finite occurrence.

          Abstract

          Harnessing the precision power of radiation therapy to cancer sites has been an important part of cancer therapies however, we are becoming more aware that radiation is not only killing cancer cells at the cancer sites but also around distant sites away from the radiation field and hence controlling the spread of cancer all over the body, the effect now known as the abscopal effect. This review seeks to elucidate to readers the different modalities of radiation, systemic therapies, and other techniques rarely explored to potentiate the abscopal effect from a mere coincidence to a finite occurrence.

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          Most cited references100

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          Calreticulin exposure dictates the immunogenicity of cancer cell death.

          Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.
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            Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.

            Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.
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              Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

              A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.
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                Author and article information

                Contributors
                vsubbiah@mdanderson.org
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                21 November 2022
                March 2023
                : 12
                : 6 ( doiID: 10.1002/cam4.v12.6 )
                : 6451-6465
                Affiliations
                [ 1 ] Department of Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer Center Houston Texas USA
                [ 2 ] Department of Oncology The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital Baltimore Maryland USA
                [ 3 ] Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston Texas USA
                Author notes
                [*] [* ] Correspondence

                Vivek Subbiah, MD, Department of Investigational Cancer Therapeutics (A Phase 1 Program), Division of Cancer Medicine, UT MD Anderson Cancer Center | 1515 Holcombe Blvd. | Unit 455 | Houston, TX 77030, USA.

                Email: vsubbiah@ 123456mdanderson.org

                Author information
                https://orcid.org/0000-0002-8227-638X
                https://orcid.org/0000-0003-4272-312X
                https://orcid.org/0000-0002-6064-6837
                Article
                CAM45454 CAM4-2022-09-4068.R2
                10.1002/cam4.5454
                10067075
                36411943
                23e2ab34-f057-4f46-a5ab-ab45fc89945c
                © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 05 November 2022
                : 16 September 2022
                : 08 November 2022
                Page count
                Figures: 2, Tables: 1, Pages: 15, Words: 10173
                Funding
                Funded by: MD Anderson Cancer Center , doi 10.13039/100007313;
                Categories
                Review
                REVIEWS
                Clinical Cancer Research
                Custom metadata
                2.0
                March 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.7 mode:remove_FC converted:02.04.2023

                Oncology & Radiotherapy
                abscopal,cancer,cellular therapy,nanoparticles,radionuclide therapy,radscopal,systemic therapy,vaccine

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