Radiotherapy and Immunotherapy Combinations for the Treatment of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 September 2021) | Viewed by 5721

Special Issue Editor


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Guest Editor
Division of Cancer Sciences, Faculty of Biology, School of Medical Sciences, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
Interests: onco-immunology

Special Issue Information

Dear Colleagues,

Radiotherapy (RT) is a principal component of cancer treatment, given to over 50% of patients. In addition to direct cytotoxic activity via the induction of DNA damage, RT can influence the immune response to cancer and recalibrate the tumour microenvironment. Immunogenic changes in response to RT contribute to multiple stages of the cancer immunity cycle, activate the innate immune system and orchestrate priming of tumour-specific immunity. Alternatively, RT can exacerbate immune suppression via the upregulation of inhibitory checkpoints, and recruitment of myeloid cells. The ability of RT to modulate immune responses to cancer provides a clear rationale for combination with immunotherapeutic strategies. An extensive array of preclinical studies support this concept, demonstrating improved local control following combination therapy and highlighting the exciting potential to augment systemic immunity, leading to remission of disease outside of the irradiated field (abscopal responses). In particular, the inclusion of immune checkpoint blockade into the RT regimen has demonstrated considerable efficacy, and combinations of RT and anti-PD1/PD-L1 or CTLA-4 antibodies are currently being evaluated in the clinical arena.

Translating the preclinical potential of RT and immunotherapy combinations into clinical reality requires a greater understanding of the biological mechanisms that underpin the impressive experimental outcomes to date. There remains much uncertainty around the optimal sequence, schedule, dose, fraction and field of RT to use together with immunotherapy. Enhanced understanding of drivers of resistance, as well as identification of biomarkers to better predict which patients will respond to treatment are also required.  

This Special Issue will highlight the role of radiotherapy in modulating the tumour microenvironment and systemic immune response to cancer, the impact of immunotherapy combination on the efficacy of RT and provide a perspective on how RT and immunotherapy combinations can be utilised to enhance patient outcome in the clinic.

Dr. Jamie Honeychurch
Guest Editor

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Keywords

  • Radiotherapy
  • Immunotherapy
  • Tumour microenvironment
  • Checkpoint blockade
  • Immune suppression
  • Immunogenic cell death

Published Papers (2 papers)

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Research

18 pages, 6428 KiB  
Article
The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent—DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors
by Alina Drzyzga, Tomasz Cichoń, Justyna Czapla, Magdalena Jarosz-Biej, Ewelina Pilny, Sybilla Matuszczak, Piotr Wojcieszek, Zbigniew Urbaś and Ryszard Smolarczyk
Cancers 2021, 13(16), 3924; https://doi.org/10.3390/cancers13163924 - 04 Aug 2021
Cited by 10 | Viewed by 2323
Abstract
Vascular disrupting agents (VDAs), such as DMXAA, effectively destroy tumor blood vessels and cause the formation of large areas of necrosis in the central parts of the tumors. However, the use of VDAs is associated with hypoxia activation and residues of rim cells [...] Read more.
Vascular disrupting agents (VDAs), such as DMXAA, effectively destroy tumor blood vessels and cause the formation of large areas of necrosis in the central parts of the tumors. However, the use of VDAs is associated with hypoxia activation and residues of rim cells on the edge of the tumor that are responsible for tumor regrowth. The aim of the study was to combine DMXAA with radiotherapy (brachytherapy) and find the appropriate administration sequence to obtain the maximum synergistic therapeutic effect. We show that the combination in which tumors were irradiated prior to VDAs administration is more effective in murine melanoma growth inhibition than in either of the agents individually or in reverse combination. For the first time, the significance of immune cells’ activation in such a combination is demonstrated. The inhibition of tumor growth is linked to the reduction of tumor blood vessels, the increased infiltration of CD8+ cytotoxic T lymphocytes and NK cells and the polarization of macrophages to the cytotoxic M1 phenotype. The reverse combination of therapeutic agents showed no therapeutic effect and even abolished the effect of DMXAA. The combination of brachytherapy and vascular disrupting agent effectively inhibits the growth of melanoma tumors but requires careful planning of the sequence of administration of the agents. Full article
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29 pages, 9660 KiB  
Article
Combinations of Radiotherapy with Vaccination and Immune Checkpoint Inhibition Differently Affect Primary and Abscopal Tumor Growth and the Tumor Microenvironment
by Michael Rückert, Lisa Deloch, Benjamin Frey, Eberhard Schlücker, Rainer Fietkau and Udo S. Gaipl
Cancers 2021, 13(4), 714; https://doi.org/10.3390/cancers13040714 - 09 Feb 2021
Cited by 26 | Viewed by 2819
Abstract
Radiotherapy (RT) is known to have immune-modulatory properties. We hypothesized that RT and inactivated whole tumor cell vaccines generated with high hydrostatic pressure (HHP) synergize to retard the tumor growth which can be additionally improved with anti-PD-1 treatment. In abscopal tumor models, we [...] Read more.
Radiotherapy (RT) is known to have immune-modulatory properties. We hypothesized that RT and inactivated whole tumor cell vaccines generated with high hydrostatic pressure (HHP) synergize to retard the tumor growth which can be additionally improved with anti-PD-1 treatment. In abscopal tumor models, we injected mice with B16-F10 melanoma or TS/A mammary tumors. To evaluate the efficiency of RT in combination with HHP vaccines, we locally irradiated only one tumor with 2 × 8 Gy or 3 × 8 Gy. HHP vaccines further retarded the growth of locally irradiated (2 × 8 Gy) tumors. However, HHP vaccination combined with RT failed to induce abscopal anti-tumor immune responses, namely those to non-irradiated tumors, and even partly abrogated those which were induced with RT plus anti-PD-1. In the latter group, the abscopal effects were accompanied by an elevated infiltration of CD8+ T cells, monocytes/macrophages, and dendritic cells. 3 × 8 Gy failed to induce abscopal effects in association with increased expression of immunosuppressive checkpoint molecules compared to 2 × 8 Gy. We conclude that HHP vaccines induce anti-tumor effects, but only if the tumor microenvironment was previously modulated by hypofractionated RT with not too many fractions, but failed to improve RT plus anti-PD-induced abscopal responses that are characterized by distinct immune alterations. Full article
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