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Review

Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold

by
William Tyler Turchan
,
Sean P. Pitroda
and
Ralph R. Weichselbaum
*
Department of Radiation and Cellular Oncology and the Ludwig Center for Metastasis Research, University of Chicago, 5758 S Maryland Ave, Chicago, IL 60637, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(17), 9573; https://doi.org/10.3390/ijms22179573
Submission received: 20 July 2021 / Revised: 26 August 2021 / Accepted: 27 August 2021 / Published: 3 September 2021
(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)
Versions Notes

Abstract

:
Radiotherapy and immunotherapy are most effective as cancer therapies in the setting of low-volume disease. Although initial studies of radio-immunotherapy in patients with metastatic cancer have not confirmed the efficacy of this approach, the role of radio-immunotherapy in patients with limited metastatic burden is unclear. We propose that further investigation of radio-immunotherapy in metastatic patients should focus upon patients with oligometastatic disease.

1. Introduction

Both radiotherapy and immunotherapy are effective as single therapies in select patients with cancer. While radiotherapy and immunotherapy differ in their indications, both treatments are most effective in patients with low-volume disease. Although adjuvant immunotherapy has been demonstrated to improve outcomes following radiotherapy in two disease sites, studies investigating the role of combined radiotherapy and immunotherapy in patients with metastatic disease have largely failed to demonstrate consistent and predictable efficacy. Patients with oligometastatic disease represent a subset of patients with metastatic cancer in whom disease burden is limited. These patients may be ideally situated to derive the greatest benefit from radio-immunotherapy. Thus, future studies utilizing radio-immunotherapy should focus upon patients with oligometastatic disease and should pursue novel means to widen the therapeutic ratio of radio-immunotherapy in this population.

2. Radiotherapy and Immunotherapy as Single Treatments: A Brief Overview

The utility of radiotherapy as a treatment for patients with cancer has been recognized for over a century [1]. Until recently the role of radiotherapy in the management of patients with metastatic disease has primarily been limited to the palliation of disease-related symptoms. However, recent data suggest that that radiotherapy may play a role in the definitive management of some patients with metastatic disease. Notably, the results of SABR-COMET, a phase II screening trial in which patients with a controlled primary tumor and ≤ 5 distant metastases (75% of patients had 1–2 metastases) were randomized to receive standard of care therapy with or without metastasis-directed ablative radiotherapy, showed that patients treated with radiotherapy had improved overall survival (OS) at five years compared to patients not receiving radiotherapy (42% vs. 18%, p = 0.006) [2]. Disease-site specific phase II randomized trials have similarly demonstrated improvements in outcomes with the addition metastasis-directed radiotherapy to standard management in patients with prostate cancer [3,4] and non-small cell lung cancer (NSCLC) [5,6]. Like SABR-COMET, these studies exclusively included patients with few distant metastases at the time of metastasis-directed radiotherapy. Although the results of ongoing confirmatory studies investigating the role of metastasis-directed radiotherapy in patients with few and several metastases separately (NCT03862911, NCT0372134, NCT02364557, NCT03137771) will provide further data, non-randomized series support the notion that low disease burden is an important predictor of long-term disease control in this population [7,8]. However, it is of note that, given some patients may require multiple interventions, OS may be a better measure of efficacy than progression-free survival (PFS) in this context.
Compared to radiotherapy, immunotherapy represents a relatively new strategy in the management of patients with cancer. Nonetheless the impact of immunotherapy has been dramatic among select populations of patients with metastatic disease. Notably, patients with metastatic melanoma treated with nivolumab and ipilimumab have recently been reported to have five-year OS of 52% [9], while the results of a recent investigation of pembrolizumab in patients with metastatic NSCLC with a programmed death-ligand 1 (PD-L1) tumor proportion score ≥ 50% demonstrate five-year OS of 30% and 25% in treatment-naive and previously treated patients, respectively [10]. These results are considerable improvements over historical results. Similar to radiotherapy, data support immunotherapy to be most efficacious in the setting of low-volume disease. Among patients treated for advanced melanoma with pembrolizumab on KEYNOTE-001, patients with less than the median baseline tumor size (summed diameter <10.2 cm) were noted to have improved overall objective response rate (ORR) (44% vs. 23%; p < 0.001) and OS (HR 0.38; p < 0.001) [11]. Thus, mounting data support the benefit of both radiotherapy and immunotherapy as monotherapies for patients with metastatic disease, especially in the setting of low disease burden.

3. What We Currently Know: Investigations of Combined Radio-Immunotherapy in Patients with Advanced Malignancies

3.1. Addition of Immunotherapy to Definitive Local Therapy

The results of a number of studies investigating various combinations of immunotherapy and radiotherapy in the definitive setting have recently been reported (Table 1). Among these studies, perhaps the best known is the PACIFIC trial, which randomized patients without progression of disease following definitive chemoradiotherapy for unresectable stage III NSCLC to adjuvant durvalumab or placebo beginning 1–42 days after the completion of chemoradiotherapy [12]. At four years, the addition of durvalumab significantly improved both PFS (35% [95% CI, 30–40%]) and OS (50% [95% CI, 45–54%] compared to placebo (20% [95% CI, 14–26%] and 36% [95% CI, 30–43%] for PFS and OS, respectively) [13]. Similarly, the recently reported CheckMate-577 trial, which randomized patients with Stage II-III esophageal and gastroesophageal junction cancer to receive adjuvant nivolumab or placebo 4–16 weeks following the completion of definitive therapy with neoadjuvant chemoradiotherapy followed by R0 resection, demonstrated improved median disease-free survival (DFS) among patients treated with nivolumab (22.4 months [95% CI, 16.6–34.0 months]), compared to those receiving placebo (11.0 months [95% CI, 9.3–14.3 months]) [14].
While the results of the PACIFIC and CheckMate-577 studies demonstrate the potential utility of immunotherapy to improve the outcomes of patients treated with radiotherapy for locally advanced malignancies, other attempts to combine radiotherapy and immunotherapy in the definitive setting have been less successful in demonstrating consistent benefits. The JAVELIN Head and Neck 100 and PembroRad trials both represent unsuccessful attempts to improve the outcomes of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) with the addition of concurrent immune checkpoint blockade (ICB) agents to definitive radiotherapy [15,16]. Similarly, the results of CheckMate-498 and Checkmate-548, which investigated the addition of concurrent nivolumab to radiotherapy in patients with O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated glioblastoma multiforme (GBM) and temozolomide and radiotherapy in patients with MGMT-methylated GBM, respectively, failed to demonstrate the efficacy of nivolumab in these settings [17,18,19,20,21]. The design and results of these studies are summarized in Table 1.
A number of potential explanations for the disparate results of studies combining radiotherapy and immunotherapy in the curative treatment of patients exist. Unlike unsuccessful trials in patients with HNSCC and GBM, the PACIFIC and CheckMate-577 trials utilized ICB in the adjuvant setting. Thus, it is possible that the inherent low volume of disease afforded by treatment in the adjuvant setting explains the difference in outcomes in the PACIFIC and CheckMate-577 trials compared to trials investigating radio-immunotherapy in patients with HNSCC and GBM. This hypothesis is bolstered by evidence that, as monotherapies, radiotherapy and immunotherapy have the greatest efficacy in patients with low-volume disease. The important benefits of adjuvant ICB in patients without evidence of residual disease following local therapy for high-risk melanoma [22,23] also support the theory that dissimilar outcomes of studies combining radiotherapy and immunotherapy in the definitive setting can be attributed to differences in disease burden. Moreover, it is of note that unlike tumors, which have been demonstrated to harbor radioresistant resident T-cells [24,25,26], T-cells in lymphoid organs, or circulating T cells, are known to be radiosensitive [25]. Draining lymph nodes have been demonstrated to facilitate anti-tumor immune response following radiotherapy by serving as sites of T-cell accumulation and priming [27]. Accordingly, studies using murine models treated with concurrent ICB and radiotherapy have demonstrated that the addition of the draining lymph nodes to the radiotherapy treatment volume results inferior OS [28]. Thus, it is conceivable that large elective nodal volumes contributed to the failure of studies investigating concurrent ICB and radiotherapy for locally advanced HNSCC [15,16].

3.2. Combined Radio-Immunotherapy in Patients with Metastatic Disease

Combined radio-immunotherapy has been investigated as a strategy for treating patients with metastatic disease. Unlike studies adding immunotherapy to radiotherapy as a means of increasing local response to radiotherapy and/or inducing anti-tumor immune effects against remaining subclinical disease, immunotherapy has primarily been investigated as a means of potentiating distant responses following radiotherapy in patients with metastatic disease. This paradigm stems from pre-clinical data demonstrating that abscopal effects at unirradiated tumor locations are mediated by T-cells [29] and that ICB prevents the development of distant metastases following radiotherapy [30]. Accordingly, a number of studies utilizing murine models have successfully induced abscopal responses following radiotherapy with the addition of ICB [31,32,33].
In contrast to the pre-clinical setting, meaningful abscopal responses are rather uncommon clinically [34]. A notable exception comes from a study reported by Golden et al. in which patients with ≥3 metastases were treated with radiotherapy to one metastasis (35 Gy in 10 fractions) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) [35]. Abscopal responses were observed in 11 of 41 enrolled patients. However, the majority of abscopal responses (defined as a decrease in the longest diameter of any measurable non-irradiated lesion by ≥30%) were rather modest [35]. It is also of note that abscopal responses primarily occurred in patients with relatively low pre-treatment disease burden in this study. Of the 11 patients in whom abscopal responses were observed, eight patients had three metastases at study enrollment (the minimum allowed) and three patients had 4–6 metastases. Further, no patients with >6 metastases experienced abscopal responses [35]. The benefit of adding metastasis-directed radiotherapy to immunotherapy has been the subject of a number of comparative phase I/II trials, the designs and results of which are summarized in Table 2. These studies represent a variety of histologies, including NSCLC [36,37,38,39], melanoma [38], HNSCC [40], and adenoid cystic carcinoma (ACC) [41]. With the exception of the report by Curti et al. in which patients received interleukin-2 (IL-2) three days after treatment with either 20 Gy or 40 Gy given in 20 Gy fractions [38], patients in these studies were treated with an anti-PD-1/PD-L1 agent [36,37,38,39,40,41]. Patients treated with radiotherapy in these studies were largely treated with radiotherapy doses of 24–30 Gy given in 3–5 fractions [36,37,40,41], with exceptions in the study reported by Welsh et al., in which patients were treated with 48 Gy in four fractions if deemed clinically feasible (n = 19) and otherwise received 45 Gy in 15 fractions (n = 21) [39], and the previously described study reported by Curti et al. Among patients treated with radiotherapy in these studies, radiotherapy was delivered before [38], following [36,37,41], between cycles [40], and concurrently [39], relative to ICB. Despite the differences among these studies, a similarity exists in that all failed to demonstrate significant improvements in ORR, PFS, and OS with the addition of radiotherapy to immunotherapy [36,37,38,39,40,41]. It is of note that, in an unplanned, pooled analysis of the studies by Theelen et al. and Welsh et al., patients treated with radiotherapy had improved PFS (4.4 vs. 9.0 months, p = 0.045) and OS (8.7 vs. 19.2 months, p < 0.001) [42]. On the whole, the results of comparative studies of radio-immunotherapy suggest that previously tested strategies for combining radiotherapy and immunotherapy rarely induce clinically meaningful abscopal responses in patients with metastatic disease.
While clinical studies investigating radio-immunotherapy in patients with metastatic disease have largely failed to demonstrate improved outcomes compared to treatment with immunotherapy alone, a number of factors may explain these results. Although comparative studies investigating the addition of radiotherapy to immunotherapy have been negative regardless of whether a single [36,37,40] or multiple metastases [38,39,41] were targeted with radiotherapy, it is of note that all of these studies have required at least one metastasis to be remain unirradiated. In contrast to these studies, in a non-randomized prospective study of NSCLC patients with ≤ 4 metastases (93% had ≤ 2 metastases and 61% had one metastasis) reported by Bauml et al., locally ablative therapy to all sites of distant metastasis in combination with pembrolizumab yielded impressive gains over historical outcomes, including a two-year PFS of 56% among patients metachronous disease [43]. Pre-clinical data also support the idea that radio-immunotherapy may be most effective when all sites of distant metastasis are targeted with radiotherapy [44]. Radiotherapy is capable of increasing tumor T-cell infiltration and killing resistant tumor clones, while sparing radioresistant resident T-cells [24,25,26]. Moreover, radiotherapy enhances major histocompatibility complex class I (MHC-I) expression [45], down regulation of which is a known mechanism of tumor immune evasion [46], and induces/up-regulates immunogenic genes [47] that may to drive response to ICB [48]. Additionally, it is possible that, similar to the adjuvant setting, radio-immunotherapy is most effective in the setting of low-volume disease. Unlike comparative studies of immunotherapy with and without radiotherapy, in which the majority of patients had relatively high-burden metastatic disease, the studies reported by Golden et al. [35] and Bauml et al. [43], respectively, primarily enrolled patients with low-volume disease. Thus, it is plausible that the failure of comparative studies to demonstrate the efficacy of radio-immunotherapy in metastatic patients can, in part, be attributed to the relatively high average disease burden of patients in these studies.

4. What the Future May Hold: Strategies to Maximize the Therapeutic Ratio of Radio-Immunotherapy in Cancer Patients Going Forward

Overall, studies investigating the utility of radiotherapy and immunotherapy in cancer patients suggest that these therapies are most efficacious, both individually and in combination, in the setting of low-volume disease. Moreover, data support the hypothesis that radio-immunotherapy is most effective when all sites of macroscopic disease are treated with radiotherapy and potentially immunosuppressive nodal irradiation is avoided. Given these criteria, patients with oligometastatic disease may be expected to derive the greatest potential benefit from radio-immunotherapy. Thus, future studies of radio-immunotherapy should focus upon this population.
The oligometastatic hypothesis, which was initially proposed in 1995 [49], predicts the existence of a state in which patients have a low volume of metastatic disease that is unlikely to progress rapidly [49]. Given that patients with oligometastatic disease inherently have a low disease burden, these individuals may be predilected to derive the greatest benefit from radio-immunotherapy. Moreover, because patients with oligometastatic cancer are more likely to have disease that can feasibly be comprehensively covered in radiotherapy treatment volumes without the need for potentially immunosuppressive large-volume nodal irradiation, these patients may be especially likely to benefit from radio-immunotherapy. As a result, future studies should be conducted to determine the role of radio-immunotherapy in the management of patients with oligometastatic cancer.
Since it was first described, the oligometastatic hypothesis has been refined in a number of ways. In addition to the volume and rate of progression, which define the oligometastatic state, a number of other features, including disease histology, lymph node status, and timing of metastasis, have been demonstrated to be prognostic in this population [50,51,52]. Thus, these factors are likely to also be important considerations in future studies of radio-immunotherapy in patients with metastatic disease. Moreover, molecular features predictive of oligo- versus poly-metastatic progression have been identified [52] and can be used to stratify patients by risk of failure following metastasis-directed local therapy [53]. Thus, future studies should utilize molecular information to identify patients most likely to benefit from radio-immunotherapy. In addition to focusing on patient populations most likely to benefit from radio-immunotherapy, future studies should also investigate novel means of widening the therapeutic ratio of radio-immunotherapy. A number of ongoing studies aim to characterize combinations of immunomodulatory agents that may be able to enhance and/or improve upon the efficacy of radio-immunotherapy regimens that utilize ICB [54]. Recent evidence also suggests that the microbiome affects anti-tumor immune responses induced by both ICB [55] and radiotherapy [56,57], and therefore this could be a point of further investigation going forward.
In conclusion, radiotherapy and immunotherapy have been shown to improve outcomes in distinct patient populations, though both therapies are seemingly most effective in patients with low-volume disease. Unlike the addition of adjuvant immunotherapy following radiotherapy, which has improved outcomes in multiple disease sites, initial studies of radio-immunotherapy in metastatic patients have not confirmed the efficacy of this approach. However, additional studies are needed to determine the role of radio-immunotherapy in patients with oligometastatic disease, given that these individuals inherently have a limited metastatic burden and may be most likely to reap the benefits of combined radiotherapy and immunotherapy.

Author Contributions

Conceptualization, R.R.W.; methodology, W.T.T., S.P.P., and R.R.W.; analysis, W.T.T., S.P.P., and R.R.W.; data curation, W.T.T., S.P.P., and R.R.W.; writing—original draft preparation, W.T.T., S.P.P., and R.R.W.; writing—review and editing, W.T.T., S.P.P., and R.R.W.; visualization, W.T.T.; supervision, R.R.W.; project administration, R.R.W.; funding acquisition, R.R.W. All authors have read and agreed to the published version of the manuscript.

Funding

We would like to acknowledge the Ludwig Cancer Research Foundation and the Foglia Family Foundation for their funding support.

Conflicts of Interest

R.R.W. has stock and other ownership interests with Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics, Oncosenescence. He has served in a consulting or advisory role for Aettis Inc., Astrazeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano proteagen, NKMax America Inc, Shuttle Pharmaceuticals, Highlight Therapeutics, S.L. He has research grants with Varian and Regeneron. He has received compensation including travel, accommodations, or expense reimbursement from Astrazeneca, Boehringer Ingelheim LTD and Merck Serono S.A. R.R.W. and S.P.P. have a patent related to methods and kits for diagnosis and triage of patients with colorectal liver metastases (WO2019204576A1). W.T.T. has no conflicts of interest.

References

  1. Connell, P.P.; Hellman, S. Advances in Radiotherapy and Implications for the Next Century: A Historical Perspective. Cancer Res. 2009, 69, 383–392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Palma, D.A.; Olson, R.; Harrow, S.; Gaede, S.; Louie, A.V.; Haasbeek, C.; Mulroy, L.; Lock, M.; Rodrigues, G.B.; Yaremko, B.P.; et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J. Clin. Oncol. 2020, 38, 2830–2838. [Google Scholar] [CrossRef] [PubMed]
  3. Ost, P.; Reynders, D.; Decaestecker, K.; Fonteyne, V.; Lumen, N.; De Bruycker, A.; Lambert, B.; Delrue, L.; Bultijnck, R.; Claeys, T.; et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J. Clin. Oncol. 2018, 36, 446–453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Phillips, R.; Shi, W.Y.; Deek, M.; Radwan, N.; Lim, S.J.; Antonarakis, E.S.; Rowe, S.P.; Ross, A.E.; Gorin, M.A.; Deville, C.; et al. Outcomes of Observation vs. Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020, 6, 650–659. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Gomez, D.R.; Tang, C.; Zhang, J.; Blumenschein, G.R., Jr.; Hernandez, M.; Lee, J.J.; Ye, R.; Palma, D.A.; Louie, A.V.; Camidge, D.R.; et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J. Clin. Oncol. 2019, 37, 1558–1565. [Google Scholar] [CrossRef] [PubMed]
  6. Iyengar, P.; Wardak, Z.; Gerber, D.E.; Tumati, V.; Ahn, C.; Hughes, R.S.; Dowell, J.E.; Cheedella, N.; Nedzi, L.; Westover, K.D.; et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018, 4, e173501. [Google Scholar] [CrossRef]
  7. Milano, M.T.; Katz, A.W.; Zhang, H.; Huggins, C.F.; Aujla, K.S.; Okunieff, P. Oligometastatic breast cancer treated with hypofractionated stereotactic radiotherapy: Some patients survive longer than a decade. Radiother. Oncol. 2019, 131, 45–51. [Google Scholar] [CrossRef]
  8. Weichselbaum, R.R. The 46th David A. Karnofsky Memorial Award Lecture: Oligometastasis—From Conception to Treatment. J. Clin. Oncol. 2018, 36, 3240–3250. [Google Scholar] [CrossRef] [PubMed]
  9. Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Rutkowski, P.; Lao, C.D.; Cowey, C.L.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2019, 381, 1535–1546. [Google Scholar] [CrossRef] [Green Version]
  10. Garon, E.B.; Hellmann, M.D.; Rizvi, N.A.; Carcereny, E.; Leighl, N.B.; Ahn, M.J.; Eder, J.P.; Balmanoukian, A.S.; Aggarwal, C.; Horn, L.; et al. Five-Year Overall Survival for Patients With Advanced NonSmall-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J. Clin. Oncol. 2019, 37, 2518–2527. [Google Scholar] [CrossRef]
  11. Joseph, R.W.; Elassaiss-Schaap, J.; Kefford, R.; Hwu, W.-J.; Wolchok, J.D.; Joshua, A.M.; Ribas, A.; Hodi, F.S.; Hamid, O.; Robert, C.; et al. Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab. Clin. Cancer Res. 2018, 24, 4960–4967. [Google Scholar] [CrossRef] [Green Version]
  12. Antonia, S.J.; Villegas, A.; Daniel, D.; Vicente, D.; Murakami, S.; Hui, R.; Yokoi, T.; Chiappori, A.; Lee, K.H.; de Wit, M.; et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2017, 377, 1919–1929. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Faivre-Finn, C.; Vicente, D.; Kurata, T.; Planchard, D.; Paz-Ares, L.; Vansteenkiste, J.F.; Spigel, D.R.; Garassino, M.C.; Reck, M.; Senan, S.; et al. Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-an Update From the PACIFIC Trial. J. Thorac. Oncol. 2021, 16, 860–867. [Google Scholar] [CrossRef] [PubMed]
  14. Kelly, R.J.; Ajani, J.A.; Kuzdzal, J.; Zander, T.; Van Cutsem, E.; Piessen, G.; Mendez, G.; Feliciano, J.; Motoyama, S.; Lièvre, A.; et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N. Engl. J. Med. 2021, 384, 1191–1203. [Google Scholar] [CrossRef] [PubMed]
  15. Lee, N.Y.; Ferris, R.L.; Psyrri, A.; Haddad, R.I.; Tahara, M.; Bourhis, J.; Harrington, K.; Chang, P.M.-H.; Lin, J.-C.; Razaq, M.A.; et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: A randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021, 22, 450–462. [Google Scholar] [CrossRef]
  16. Bourhis, J.; Sire, C.; Tao, Y.; Martin, L.; Alfonsi, M.; Prevost, J.B.; Rives, M.; Lafond, C.; Tourani, J.M.; Biau, J.; et al. LBA38 Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the GORTEC 2015–01 “PembroRad” randomized trial. Ann. Oncol. 2020, 31. [Google Scholar] [CrossRef]
  17. Sampson, J.H.; Padula Omuro, A.M.; Preusser, M.; Lim, M.; Butowski, N.A.; Cloughesy, T.F.; Strauss, L.C.; Latek, R.R.; Paliwal, P.; Weller, M.; et al. A randomized, phase 3, open-label study of nivolumab versus temozolomide (TMZ) in combination with radiotherapy (RT) in adult patients (pts) with newly diagnosed, O-6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma (GBM): CheckMate-498. J. Clin. Oncol. 2016, 34, TPS2079. [Google Scholar] [CrossRef]
  18. Weller, M.; Vlahovic, G.; Khasraw, M.; Brandes, A.A.; Zwirtes, R.; Tatsuoka, K.; Carpentier, A.F.; Reardon, D.A.; Bent, M. A randomized phase 2, single-blind study of temozolomide (TMZ) and radiotherapy (RT) combined with nivolumab or placebo (PBO) in newly diagnosed adult patients (pts) with tumor O6-methylguanine DNA methyltransferase (MGMT)-methylated glioblastoma (GBM)—CheckMate-548. Ann. Oncol. 2016, 27. [Google Scholar] [CrossRef]
  19. Bristol-Myers Squibb Provides Update on Phase 3 Opdivo (Nivolumab) CheckMate -548 Trial in Patients with Newly Diagnosed MGMT-Methylated Glioblastoma Multiforme. 2019. Available online: https://news.bms.com/news/corporate-financial/2019/Bristol-Myers-Squibb-Provides-Update-on-Phase-3-Opdivo-nivolumab-CheckMate--548-Trial-in-Patients-with-Newly-Diagnosed-MGMT-Methylated-Glioblastoma-Multiforme/default.aspx (accessed on 20 August 2021).
  20. Bristol Myers Squibb Announces Update on Phase 3 CheckMate -548 Trial Evaluating Patients with Newly Diagnosed MGMT-Methylated Glioblastoma Multiforme. 2020. Available online: https://news.bms.com/news/corporate-financial/2020/Bristol-Myers-Squibb-Announces-Update-on-Phase-3-CheckMate--548-Trial-Evaluating-Patients-with-Newly-Diagnosed-MGMT-Methylated-Glioblastoma-Multiforme/default.aspx (accessed on 20 August 2021).
  21. An Investigational Immuno-therapy Study of Nivolumab Compared to Temozolomide, Each Given With Radiation Therapy, for Newly-Diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate 498); ClinicalTrials.gov: Bethesda, MA, USA, 2021.
  22. Eggermont, A.M.; Chiarion-Sileni, V.; Grob, J.J.; Dummer, R.; Wolchok, J.D.; Schmidt, H.; Hamid, O.; Robert, C.; Ascierto, P.A.; Richards, J.M.; et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N. Engl. J. Med. 2016, 375, 1845–1855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Zimmer, L.; Livingstone, E.; Hassel, J.C.; Fluck, M.; Eigentler, T.; Loquai, C.; Haferkamp, S.; Gutzmer, R.; Meier, F.; Mohr, P.; et al. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2020, 395, 1558–1568. [Google Scholar] [CrossRef]
  24. Deng, L.; Liang, H.; Xu, M.; Yang, X.; Burnette, B.; Arina, A.; Li, X.D.; Mauceri, H.; Beckett, M.; Darga, T.; et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity 2014, 41, 843–852. [Google Scholar] [CrossRef] [Green Version]
  25. Arina, A.; Beckett, M.; Fernandez, C.; Zheng, W.; Pitroda, S.; Chmura, S.J.; Luke, J.J.; Forde, M.; Hou, Y.; Burnette, B.; et al. Tumor-reprogrammed resident T cells resist radiation to control tumors. Nat. Commun. 2019, 10, 3959. [Google Scholar] [CrossRef] [Green Version]
  26. Wray, J.; Hawamdeh, R.F.; Hasija, N.; Dagan, R.; Yeung, A.R.; Lightsey, J.L.; Okunieff, P.; Daily, K.C.; George, T.J.; Zlotecki, R.A.; et al. Stereotactic body radiation therapy for oligoprogression of metastatic disease from gastrointestinal cancers: A novel approach to extend chemotherapy efficacy. Oncol. Lett. 2017, 13, 1087–1094. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Takeshima, T.; Chamoto, K.; Wakita, D.; Ohkuri, T.; Togashi, Y.; Shirato, H.; Kitamura, H.; Nishimura, T. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: Its potentiation by combination with Th1 cell therapy. Cancer Res. 2010, 70, 2697–2706. [Google Scholar] [CrossRef] [Green Version]
  28. Marciscano, A.E.; Ghasemzadeh, A.; Nirschl, T.R.; Theodros, D.; Kochel, C.M.; Francica, B.J.; Muroyama, Y.; Anders, R.A.; Sharabi, A.B.; Velarde, E.; et al. Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy. Clin. Cancer Res. 2018, 24, 5058–5071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Demaria, S.; Ng, B.; Devitt, M.L.; Babb, J.S.; Kawashima, N.; Liebes, L.; Formenti, S.C. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Onco.l Biol. Phys. 2004, 58, 862–870. [Google Scholar] [CrossRef] [PubMed]
  30. Demaria, S.; Kawashima, N.; Yang, A.M.; Devitt, M.L.; Babb, J.S.; Allison, J.P.; Formenti, S.C. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 2005, 11, 728–734. [Google Scholar] [PubMed]
  31. Park, S.S.; Dong, H.; Liu, X.; Harrington, S.M.; Krco, C.J.; Grams, M.P.; Mansfield, A.S.; Furutani, K.M.; Olivier, K.R.; Kwon, E.D. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer Immunol. Res. 2015, 3, 610–619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Deng, L.; Liang, H.; Burnette, B.; Beckett, M.; Darga, T.; Weichselbaum, R.R.; Fu, Y.X. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 2014, 124, 687–695. [Google Scholar] [CrossRef] [PubMed]
  33. Vanpouille-Box, C.; Diamond, J.M.; Pilones, K.A.; Zavadil, J.; Babb, J.S.; Formenti, S.C.; Barcellos-Hoff, M.H.; Demaria, S. TGFbeta Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity. Cancer Res. 2015, 75, 2232–2242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Abuodeh, Y.; Venkat, P.; Kim, S. Systematic review of case reports on the abscopal effect. Curr. Probl. Cancer 2016, 40, 25–37. [Google Scholar] [CrossRef] [PubMed]
  35. Golden, E.B.; Chhabra, A.; Chachoua, A.; Adams, S.; Donach, M.; Fenton-Kerimian, M.; Friedman, K.; Ponzo, F.; Babb, J.S.; Goldberg, J.; et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: A proof-of-principle trial. Lancet Oncol. 2015, 16, 795–803. [Google Scholar] [CrossRef]
  36. Moreno, V.; Gil-Martin, M.; Johnson, M.; Aljumaily, R.; Lopez-Criado, M.P.; Northfelt, D.; Crittenden, M.; Jabbour, S.; Rosen, L.; Calvo, E.; et al. MA04.01 Cemiplimab, a Human Monoclonal Anti-PD-1, Alone or in Combination with Radiotherapy: Phase 1 NSCLC Expansion Cohorts. J. Thorac. Oncol. 2018, 13, S366. [Google Scholar] [CrossRef] [Green Version]
  37. Theelen, W.; Peulen, H.M.U.; Lalezari, F.; van der Noort, V.; de Vries, J.F.; Aerts, J.; Dumoulin, D.W.; Bahce, I.; Niemeijer, A.N.; de Langen, A.J.; et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs. Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019, 5, 1276–1282. [Google Scholar] [CrossRef] [PubMed]
  38. Curti, B.; Crittenden, M.; Seung, S.K.; Fountain, C.B.; Payne, R.; Chang, S.; Fleser, J.; Phillips, K.; Malkasian, I.; Dobrunick, L.B.; et al. Randomized phase II study of stereotactic body radiotherapy and interleukin-2 versus interleukin-2 in patients with metastatic melanoma. J. Immunother. Cancer 2020, 8, e000773. [Google Scholar] [CrossRef]
  39. Welsh, J.; Menon, H.; Chen, D.; Verma, V.; Tang, C.; Altan, M.; Hess, K.; de Groot, P.; Nguyen, Q.N.; Varghese, R.; et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: A randomized phase I/II trial. J. Immunother. Cancer 2020, 8, e001001. [Google Scholar] [CrossRef]
  40. McBride, S.; Sherman, E.; Tsai, C.J.; Baxi, S.; Aghalar, J.; Eng, J.; Zhi, W.I.; McFarland, D.; Michel, L.S.; Young, R.; et al. Randomized Phase II Trial of Nivolumab With Stereotactic Body Radiotherapy Versus Nivolumab Alone in Metastatic Head and Neck Squamous Cell Carcinoma. J. Clin. Oncol. 2021, 39, 30–37. [Google Scholar] [CrossRef] [PubMed]
  41. Mahmood, U.; Bang, A.; Chen, Y.H.; Mak, R.H.; Lorch, J.H.; Hanna, G.J.; Nishino, M.; Manuszak, C.; Thrash, E.M.; Severgnini, M.; et al. A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2021, 109, 134–144. [Google Scholar] [CrossRef]
  42. Theelen, W.; Chen, D.; Verma, V.; Hobbs, B.P.; Peulen, H.M.U.; Aerts, J.; Bahce, I.; Niemeijer, A.L.N.; Chang, J.Y.; de Groot, P.M.; et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: A pooled analysis of two randomised trials. Lancet Respir. Med. 2020. [Google Scholar] [CrossRef]
  43. Bauml, J.M.; Mick, R.; Ciunci, C.; Aggarwal, C.; Davis, C.; Evans, T.; Deshpande, C.; Miller, L.; Patel, P.; Alley, E.; et al. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer: A Phase 2 Trial. JAMA Oncol. 2019. [Google Scholar] [CrossRef] [PubMed]
  44. Chuong, M.; Chang, E.T.; Choi, E.Y.; Mahmood, J.; Lapidus, R.G.; Davila, E.; Carrier, F. Exploring the Concept of Radiation “Booster Shot” in Combination with an Anti-PD-L1 mAb to Enhance Anti-Tumor Immune Effects in Mouse Pancreas Tumors. J. Clin. Oncol. Res. 2017, 5, 1058. [Google Scholar]
  45. Reits, E.A.; Hodge, J.W.; Herberts, C.A.; Groothuis, T.A.; Chakraborty, M.; Wansley, E.K.; Camphausen, K.; Luiten, R.M.; de Ru, A.H.; Neijssen, J.; et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 2006, 203, 1259–1271. [Google Scholar] [CrossRef] [PubMed]
  46. Dhatchinamoorthy, K.; Colbert, J.D.; Rock, K.L. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Front. Immunol. 2021, 12, 636568. [Google Scholar] [CrossRef] [PubMed]
  47. Lhuillier, C.; Rudqvist, N.-P.; Yamazaki, T.; Zhang, T.; Charpentier, M.; Galluzzi, L.; Dephoure, N.; Clement, C.C.; Santambrogio, L.; Zhou, X.K.; et al. Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control. J. Clin. Investig. 2021, 131, e138740. [Google Scholar] [CrossRef] [PubMed]
  48. Schumacher, T.N.; Schreiber, R.D. Neoantigens in cancer immunotherapy. Science 2015, 348, 69–74. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Hellman, S.; Weichselbaum, R.R. Oligometastases. J. Clin. Oncol. 1995, 13, 8–10. [Google Scholar] [CrossRef]
  50. Ashworth, A.B.; Senan, S.; Palma, D.A.; Riquet, M.; Ahn, Y.C.; Ricardi, U.; Congedo, M.T.; Gomez, D.R.; Wright, G.M.; Melloni, G.; et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin. Lung Cancer 2014, 15, 346–355. [Google Scholar] [CrossRef]
  51. Fong, Y.; Fortner, J.; Sun, R.L.; Brennan, M.F.; Blumgart, L.H. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann. Surg. 1999, 230, 309–318, discussion 318–21. [Google Scholar] [CrossRef] [PubMed]
  52. Lussier, Y.A.; Khodarev, N.N.; Regan, K.; Corbin, K.; Li, H.; Ganai, S.; Khan, S.A.; Gnerlich, J.L.; Darga, T.E.; Fan, H.; et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS ONE 2012, 7, e50141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Pitroda, S.P.; Khodarev, N.N.; Huang, L.; Uppal, A.; Wightman, S.C.; Ganai, S.; Joseph, N.; Pitt, J.; Brown, M.; Forde, M.; et al. Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nat. Commun. 2018, 9, 1793. [Google Scholar] [CrossRef] [PubMed]
  54. Romano, E.; Honeychurch, J.; Illidge, T.M. Radiotherapy–Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery? Cancers 2021, 13, 457. [Google Scholar] [CrossRef] [PubMed]
  55. Matson, V.; Fessler, J.; Bao, R.; Chongsuwat, T.; Zha, Y.; Alegre, M.L.; Luke, J.J.; Gajewski, T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018, 359, 104–108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Uribe-Herranz, M.; Rafail, S.; Beghi, S.; Gil-de-Gómez, L.; Verginadis, I.; Bittinger, K.; Pustylnikov, S.; Pierini, S.; Perales-Linares, R.; Blair, I.A.; et al. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. J. Clin. Investig. 2019, 130, 466–479. [Google Scholar] [CrossRef] [PubMed]
  57. Yang, K.; Hou, Y.; Zhang, Y.; Liang, H.; Sharma, A.; Zheng, W.; Wang, L.; Torres, R.; Tatebe, K.; Chmura, S.J.; et al. Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation. J. Exp. Med. 2021, 218, e20201915. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Studies of radiotherapy with and without immunotherapy in patients with locoregionally advanced cancer.
Table 1. Studies of radiotherapy with and without immunotherapy in patients with locoregionally advanced cancer.
StudyPopulationDesignResults
PACIFIC [13]n = 713,
Unresectable Stage III NSCLC a		Definitive chemo-RT ± adjuvant durvalumab starting 1–42 days laterMedian follow-up: 34.2 mo
PFS: HR 0.55 [95% CI 0.44–0.67]
OS: HR 0.71 [95% CI 0.57–0.88]
CheckMate-577 [14]n = 794,
Stage II-III
Esophageal/GEJ		Neoadjuvant chemo-RT and R0 resection ± adjuvant nivolumab starting 4–16 weeks later bMedian follow-up: 24.4 mo
DFS: HR 0.69 [95% CI 0.56–0.86]
JAVELIN
H&N 100 [15]		n = 697,
LA HNSCC		Definitive chemo-RT ± concurrent and adjuvant avelumabMedian follow-up: 14.6 mo
PFS: HR 1.21 [95% CI 0.93–1.57]
OS: HR 1.31 [95% CI 0.93–1.85]
PembroRad [16]n = 131,
LA HNSCC		Definitive concurrent RT + cetuximab vs. RT + pembrolizumabMedian follow-up: 25 mo
PFS: HR 0.83 [95% CI 0.53–1.29]
OS: HR 0.83 [95% CI 0.49–1.40]
CheckMate-498 [17]n = 560
MGMT-um GBM		Definitive concurrent RT + TMZ vs. RT + nivolumabPFS: HR 1.38 [95% CI 1.15–1.65] c
OS: HR 1.31 [95% CI 1.09–1.58] c
CheckMate-548 [18]n = 693,
MGMT-m GBM		Definitive concurrent RT + TMZ ± concurrent nivolumabPFS: NS [19]
OS: NS [20]
NSCLC = non-small-cell lung cancer, chemo-RT = chemoradiotherapy, mo = months, PFS = progression-free survival, HR = hazard ratio, 95% CI = 95% confidence interval, OS = overall survival, GEJ = gastroesophageal junction, R0 resection = microscopically margin-negative, DFS = disease-free survival, H&N = head and neck, LA HNSCC = locally advanced head and neck squamous cell carcinoma, RT = radiotherapy. MGMT-um = O6-methylguanine-DNA methyltransferase-unmethylated, GBM = glioblastoma multiforme, TMZ = temozolomide, MGMT-m = O6-methylguanine-DNA methyltransferase-methylated, NS = non-significant. a In order to be eligible for the PACIFIC trial, patients had to have no evidence of disease progression following definitive chemoradiotherapy. b In order to be eligible for CheckMate-577 patients had to have residual pathologic disease at the time of resection. c Preliminary results of CheckMate-498 are available on ClinicalTrials.gov; Identifier: NCT02617589 [21].
Table
Table 2. Studies of immunotherapy with or without radiotherapy in patients with metastatic cancer.
Table 2. Studies of immunotherapy with or without radiotherapy in patients with metastatic cancer.
Author,
Year		PopulationDesignA(RT + ICB VS. ICB) a
Moreno et al.,
2018 [36]		n = 20/33, b
Met NSCLC		Cemiplimab ± 9 Gy × 3 to 1 lesion; RT given within 1 week of ICB18% vs. 40% (NS)
Theelen et al.,
2019 c [37]		n = 76,
Met NSCLC		Pembrolizumab ± 8 Gy × 3 to 1 lesion; RT given within 1 week of ICB36% vs. 18% (p = 0.07)
Curti et al.,
2020 [38]		n = 44,
Met Melanoma		IL-2 ± 20 Gy × 1–2 to 1–3 lesions; RT given 3 days prior to IL-254% vs. 35% (NS)
Mcbride et al.,
2020 [40]		n = 62,
Met HNSCC		Nivolumab ± 9 Gy × 3 to 1 lesion; RT given between cycles 1 and 2 of ICB29% vs. 35% (p = 0.86)
Welsh et al.,
2020 c [39]		n = 20/80, d
Met NSCLC		Pembrolizumab ± RT e to 1–4 lesions; RT given concurrent with cycle 1 of ICB22% vs. 25% (p = 0.99)
Mahmood et al.,
2021 [41]		n = 20,
Met ACC		Pembrolizumab ± 6 Gy × 5 to 1–5 lesions; RT given within 1 week of ICB50% vs. 70% (p = 0.65)
RT = radiotherapy, ICB = immune checkpoint blockade, Met = metastatic, NSCLC = non-small-cell lung cancer, Gy = Gray, NS = non-significant, IL-2 = interleukin-2, HNSCC = head and neck squamous cell carcinoma, ACC = adenoid cystic carcinoma, a Out-of-field objective response rates for patients treated with radiotherapy and immunotherapy and immunotherapy alone, respectively. b The report by Moreno et al. includes the results of two separate non-randomized phase I expansion cohorts in which patients were treated with radiotherapy and pembrolizumab and pembrolizumab alone, respectively. c An unplanned pooled analysis of the studies by Theelen et al. and Welsh et al. was performed and demonstrated improved progression-free survival (4.4 vs. 9.0 months, p = 0.045) and overall survival (8.7 vs. 19.2 months, p < 0.001) with the addition of radiotherapy to pembrolizumab compared to pembrolizumab alone [42]. d The study reported by Welsh et al. included 20 patients in the initial phase 1 component. 80 patients randomized in the subsequent phase II portion. e Patients randomized to randomized to pembrolizumab and radiotherapy in the study reported by Welsh et al. were treated with a radiotherapy dose of 12.5 Gy × 4 if deemed clinically feasible (n = 19) and otherwise were treated with 3 Gy × 15 (n = 21).
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Turchan, W.T.; Pitroda, S.P.; Weichselbaum, R.R. Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold. Int. J. Mol. Sci. 2021, 22, 9573. https://doi.org/10.3390/ijms22179573

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Turchan WT, Pitroda SP, Weichselbaum RR. Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold. International Journal of Molecular Sciences. 2021; 22(17):9573. https://doi.org/10.3390/ijms22179573

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Turchan, William Tyler, Sean P. Pitroda, and Ralph R. Weichselbaum. 2021. "Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold" International Journal of Molecular Sciences 22, no. 17: 9573. https://doi.org/10.3390/ijms22179573

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Turchan, W. T., Pitroda, S. P., & Weichselbaum, R. R. (2021). Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold. International Journal of Molecular Sciences, 22(17), 9573. https://doi.org/10.3390/ijms22179573

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