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Biomedicines
Special Issues
The Synergy of Radiotherapy and Immunotherapy
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The Synergy of Radiotherapy and Immunotherapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 13916

Special Issue Editors

Dr. Eric J. Lehrer

E-Mail Website
Guest Editor
Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Interests: central nervous system malignancies; oligometastases; metastatic cancer; epidemiology; stereotactic radiosurgery; stereotactic body radiation therapy; immunotherapy; prostate cancer; gastrointestinal malignancies; biostatistics
Dr. Daniel M. Trifiletti

E-Mail Website
Guest Editor
Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
Interests: central nervous system malignancies; stereotactic radiosurgery; immunotherapy; tumor microenvironment; functional radiosurgery; clinical trials; novel cellular therapies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In addition to its local effects, radiation therapy (RT) has the ability to act as an immune modulator. Studies have demonstrated that immunologic cell death in response to ionizing radiation allows for increased anti-tumor T-cell activation. Additionally, RT has been shown to induce immune-stimulatory and/or immune-suppressive modifications in the tumor microenvironment. However, RT alone is not always adequate to overcome these immunosuppressive mechanisms. Immune checkpoint inhibitors (ICIs) have demonstrated improvements in overall survival for multiple advanced malignancies and are now frequently used in this setting. In 2011, ipilimumab was the first ICI approved by the US Food and Drug Administration. Ipilimumab is a monoclonal antibody to CTLA-4, which serves as a regulator of T-cell activation. Subsequently, agents targeting the PD-1/PD-L1 axis were approved. Due to their properties, ICIs have the potential to reverse the immune exhaustion that occurs following chronic T-cell activation. Thus, RT and ICIs can behave synergistically to enhance anti-tumor immunity.

We encourage contributors to submit manuscripts addressing any of the different aspects of radiation therapy and/or immunotherapy, including:

  • Clinical strategies to enhance the therapeutic efficacy of radiation therapy and immunotherapy.
  • Novel insights into molecular pathways and/or targets involved in the response to radiation therapy and/or immunotherapy.
  • Novel applications combining radiation therapy and immunotherapy.
  • Preclinical and translational studies.

Dr. Eric J. Lehrer
Dr. Daniel M. Trifiletti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • radiation therapy
  • radiosurgery
  • immunotherapy
  • cancer
  • immune checkpoint inhibitors
  • stereotactic body radiation therapy
  • tumor microenvironment

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Published Papers (5 papers)

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Research

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8 pages, 10081 KiB  
Article
Combination of Pembrolizumab and Stereotactic Body Radiation Therapy in Recurrent Metastatic Penile Squamous Cell Carcinoma: A Case Study
by Dalia Kaakour, Steven Seyedin, Roozbeh Houshyar and Nataliya Mar
Biomedicines 2022, 10(12), 3033; https://doi.org/10.3390/biomedicines10123033 - 24 Nov 2022
Cited by 2 | Viewed by 1627
Abstract
The prognosis for patients with penile squamous cell carcinoma metastatic to regional lymph nodes or distant sites remains poor with limited treatment options, especially after the failure of first-line chemotherapy. Clinical trials evaluating the use of checkpoint inhibitor therapy, or the use of [...] Read more.
The prognosis for patients with penile squamous cell carcinoma metastatic to regional lymph nodes or distant sites remains poor with limited treatment options, especially after the failure of first-line chemotherapy. Clinical trials evaluating the use of checkpoint inhibitor therapy, or the use of checkpoint inhibitor therapy with stereotactic body radiation therapy for the treatment of metastatic penile squamous cell carcinoma, are currently unavailable. In this case report, we present a patient with relapsed advanced penile squamous cell carcinoma and an unknown (human papilloma virus) HPV status and borderline programmed death-ligand 1 (PD-L)1 status who was treated with pembrolizumab and stereotactic body radiation therapy. This patient achieved a complete durable treatment response despite having genomic features of an immunologically “cold” tumor. This case highlights the importance of investigating more into the treatment of these tumors that lack genomic features that classically have been observed to be susceptible to treatment with immunotherapy or immunotherapy augmented with stereotactic body radiation therapy in solid tumors, particularly in metastatic penile squamous cell carcinoma. Full article
(This article belongs to the Special Issue The Synergy of Radiotherapy and Immunotherapy)
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11 pages, 889 KiB  
Article
Oligoprogression of Solid Tumors on Immune Checkpoint Inhibitors: The Impact of Local Ablative Radiation Therapy
by Kunal K. Sindhu, Anthony D. Nehlsen, Eric J. Lehrer, Jared P. Rowley, Richard G. Stock, Matthew D. Galsky and Michael Buckstein
Biomedicines 2022, 10(10), 2481; https://doi.org/10.3390/biomedicines10102481 - 5 Oct 2022
Cited by 9 | Viewed by 2120
Abstract
The breakthrough of a limited number of clones while on immune checkpoint inhibitors (ICIs), known as oligoprogression, has been previously described. The benefit of ablative radiation therapy (RT) directed at these clones, as opposed to changing systemic therapy, is unclear. We analyzed 30 [...] Read more.
The breakthrough of a limited number of clones while on immune checkpoint inhibitors (ICIs), known as oligoprogression, has been previously described. The benefit of ablative radiation therapy (RT) directed at these clones, as opposed to changing systemic therapy, is unclear. We analyzed 30 patients with advanced solid tumors, the majority of whom (23/30, 86.7%) had either hepatocellular or urothelial carcinoma, who experienced oligoprogression on ICIs and were referred for RT. In this study, oligoprogression was defined as having experienced progression at three or fewer metastatic sites outside of the brain after achieving at least stable disease on ICIs for a minimum of three months. The median time to oligoprogression was 11.1 months from the initiation of immunotherapy. 24 patients had one oligoprogressive lesion and six had two. The median radiation dose delivered was 4650 cGy in a median of five fractions. The median progression-free survival (PFS) after RT was 7.1 months, and the time to oligoprogression was not a significant predictor of PFS2. 26 patients continued on ICIs after RT. While 17 patients subsequently progressed, 15 did so at three or fewer metastatic sites and could have theoretically stood to benefit from an additional course of salvage RT to further extend the lifespan of their ICIs. Overall survival at 6, 12, and 24 months was 100.0%, 96.3%, and 82.8%, respectively. These results suggest that RT may provide a PFS benefit and extend the lifespan of ICIs in patients who experience oligoprogression. Regardless of PFS, however, overall survival in this population appears to be excellent. Full article
(This article belongs to the Special Issue The Synergy of Radiotherapy and Immunotherapy)
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25 pages, 7899 KiB  
Article
Development of In Vitro Assays for Advancing Radioimmunotherapy against Brain Tumors
by Yohan Walter, Anne Hubbard, Allie Benoit, Erika Jank, Olivia Salas, Destiny Jordan and Andrew Ekpenyong
Biomedicines 2022, 10(8), 1796; https://doi.org/10.3390/biomedicines10081796 - 26 Jul 2022
Cited by 3 | Viewed by 3321
Abstract
Glioblastoma (GBM) is the most common primary brain tumor. Due to high resistance to treatment, local invasion, and a high risk of recurrence, GBM patient prognoses are often dismal, with median survival around 15 months. The current standard of care is threefold: surgery, [...] Read more.
Glioblastoma (GBM) is the most common primary brain tumor. Due to high resistance to treatment, local invasion, and a high risk of recurrence, GBM patient prognoses are often dismal, with median survival around 15 months. The current standard of care is threefold: surgery, radiation therapy, and chemotherapy with temozolomide (TMZ). However, patient survival has only marginally improved. Radioimmunotherapy (RIT) is a fourth modality under clinical trials and aims at combining immunotherapeutic agents with radiotherapy. Here, we develop in vitro assays for the rapid evaluation of RIT strategies. Using a standard cell irradiator and an Electric Cell Impedance Sensor, we quantify cell migration following the combination of radiotherapy and chemotherapy with TMZ and RIT with durvalumab, a PD-L1 immune checkpoint inhibitor. We measure cell survival using a cloud-based clonogenic assay. Irradiated T98G and U87 GBM cells migrate significantly (p < 0.05) more than untreated cells in the first 20–40 h post-treatment. Addition of TMZ increases migration rates for T98G at 20 Gy (p < 0.01). Neither TMZ nor durvalumab significantly change cell survival in 21 days post-treatment. Interestingly, durvalumab abolishes the enhanced migration effect, indicating possible potency against local invasion. These results provide parameters for the rapid supplementary evaluation of RIT against brain tumors. Full article
(This article belongs to the Special Issue The Synergy of Radiotherapy and Immunotherapy)
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Review

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12 pages, 291 KiB  
Review
A Review of the Role of Stereotactic Radiosurgery and Immunotherapy in the Management of Primary Central Nervous System Tumors
by Eric J. Lehrer, Brianna M. Jones, Kunal K. Sindhu, Daniel R. Dickstein, Mira Cohen, Stanislav Lazarev, Alfredo Quiñones-Hinojosa, Sheryl Green and Daniel M. Trifiletti
Biomedicines 2022, 10(11), 2977; https://doi.org/10.3390/biomedicines10112977 - 19 Nov 2022
Cited by 4 | Viewed by 2388
Abstract
Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs) are widely used in the management of brain metastases. These therapies are commonly administered concurrently; as SRS may enhance anti-tumor immunity and responsiveness to ICIs. However, the use of ICIs with and without SRS in [...] Read more.
Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs) are widely used in the management of brain metastases. These therapies are commonly administered concurrently; as SRS may enhance anti-tumor immunity and responsiveness to ICIs. However, the use of ICIs with and without SRS in the management of primary brain tumors remains a controversial topic. Meningiomas are the most common nonmalignant and extra-parenchymal brain tumor, which often respond well to surgery and radiotherapy. However, higher grade meningiomas tend to be resistant to these treatments, and the use of chemotherapy and targeted agents in this setting have yielded disappointing results. Thus, there is heightened interest in the utilization of ICIs. Glioblastoma is the most common malignant primary intraparenchymal brain tumor. It is associated with a grim prognosis with a median overall survival of approximately 20 months, despite optimal therapy. While SRS in the adjuvant setting, and ICI in the recurrent setting, have failed to demonstrate a survival benefit, SRS in the preoperative setting has the potential to enhance anti-tumor immunity and responsiveness to ICIs. Thus, these treatments represent an attractive option to add to the armamentarium of meningioma and glioblastoma management. In this review, we provide a detailed overview of the evidence supporting the use of ICIs and SRS in each of these settings. Full article
(This article belongs to the Special Issue The Synergy of Radiotherapy and Immunotherapy)
13 pages, 709 KiB  
Review
Combining Radiotherapy and Immunotherapy in Metastatic Breast Cancer: Current Status and Future Directions
by Steven David, Jennifer Tan, Shankar Siva, Lama Karroum, Peter Savas and Sherene Loi
Biomedicines 2022, 10(4), 821; https://doi.org/10.3390/biomedicines10040821 - 31 Mar 2022
Cited by 8 | Viewed by 3443
Abstract
The role of radiotherapy and immunotherapy with immune checkpoint inhibitors (ICI) is of emerging interest in many solid tumours, including breast cancer. There is increasing evidence that the host’s immune system plays an important role in influencing the response to treatment and prognosis [...] Read more.
The role of radiotherapy and immunotherapy with immune checkpoint inhibitors (ICI) is of emerging interest in many solid tumours, including breast cancer. There is increasing evidence that the host’s immune system plays an important role in influencing the response to treatment and prognosis in breast cancer. Several pre-clinical studies and clinical trials have reported on the ‘abscopal effect—regression of distant untreated tumour sites, mediated by an immunological response following ionizing radiation to a targeted tumour site. Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive technique used to augment various immune responses with an ablative tumoricidal dose when compared to conventional radiotherapy. SABR is characterized by typically 1–5 precision radiotherapy treatments that simultaneously deliver a high dose, whilst sparing normal tissues. Following SABR, there is evidence of systemic immune activation in patients with increased PD1 expression on CD8+ and CD4+ T cells. Studies continue to focus on metastatic triple-negative disease, a highly immunogenic subtype of breast cancer with poor prognosis. In this review, we discuss the immunological effect of SABR, alone and in combination with immunotherapy, and the importance of dose and fractionation. We also propose future strategies for treating oligometastatic disease, where this approach may be most useful for producing durable responses. Full article
(This article belongs to the Special Issue The Synergy of Radiotherapy and Immunotherapy)
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