Radiation Therapy and the In Situ Vaccination Approach

Golden, Encouse B.; Marciscano, Ariel E.; Formenti, Silvia C.

doi:10.1016/j.ijrobp.2020.08.023

Cited by 50 publications

(39 citation statements)

References 89 publications

(97 reference statements)

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“…RT is a well-known immune modulator that can provide danger signals to awaken the immune system [ 19 , 21 , 22 ]. Numerous preclinical cancer models including our research in brain and prostate tumor models have shown that RT can change the TME [ 22 , 28 , 32 , 33 , 34 , 35 , 36 , 37 ] and provoke anti-tumor immune responses locally and systemically [ 26 , 28 , 38 , 39 , 40 ]. To examine the effect of RT on the immune microenvironment of UN-KC-6141 tumors, the expression of CD8 and CD4 in control, SHD-RT-, or F-RT-treated tumors was examined by immunohistochemical (IHC) staining.…”

Section: Resultsmentioning

confidence: 99%

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

Lee

Yang

et al. 2021

IJMS

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The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.

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Section: Resultsmentioning

confidence: 99%

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

Lee

Yang

et al. 2021

IJMS

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“…Radiotherapy is shown to cause tumor cell death associated with releasing tumor-associated antigens (TAAs), danger signals and cytokines which are highly immunogenic and related with initiation of an in-situ vaccine (11). The ionizing radiation can promote tumor cells releasing TAAs, especially tumor neoantigens (TNAs), into blood and induce immunogenic cell death (ICD) (12,13).…”

Section: Ionizing Radiation Coverts Tumor Into An In-situ Vaccinementioning

confidence: 99%

Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers

Kong

Zhao

et al. 2021

Front. Oncol.

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Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1) have been approved for a variety of malignant tumors and are widely used to treat patients with metastatic disease. However, the efficacy of PD-1 inhibitors is limited due to tumor heterogeneity, high tumor burden, and “cold” tumor microenvironment. Radiotherapy can improve the anti-tumor effects of PD-1/PD-L1 inhibitors in various ways. As a new radiotherapy method, stereotactic body radiotherapy (SBRT) or hypofractionated radiotherapy (HFRT) provides higher doses per fraction to the target lesions, thus achieving immune activation effects and overcoming tumor resistance to anti-PD-1/PD-L1 treatment, which significantly improves the local and distant control of tumors. However, for different metastatic situations, radiotherapy plays different roles in the combination therapy. In oligometastatic status, radiotherapy can be used as a local radical treatment aiming to eliminate cancers in cooperation with systemic PD-1 inhibitors. In other circumstances, like bulky metastasis or multiple metastatic tumors, radiotherapy can be used as adjuvant to systemic immunotherapy. This review focuses on the underlying mechanisms and optimization strategies for the combination of radiotherapy and anti-PD-1/PD-L1 therapy in metastatic disease.

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“…Mechanistically, TLR can enhance DC-mediated cross-presentation and activation of T cells. Novel formulations of TLR agonists with reduced toxicity and precise and image-guided radiation techniques are favorable aspects for this strategy (30,31).…”

Section: Central Role Of Dendritic Cell Maturation In Radiation-inducmentioning

confidence: 99%

“…The next generation of clinical trials addressing radiotherapy-immunotherapy combinations will have to include immunological read-outs with proper endpoints for immune monitoring as well as the identification of immune biomarkers that optimize the selection of treatment strategies (31,51).…”

Section: Addressing the Evasive Objective Of Durable Responses Of Radmentioning

confidence: 99%

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies

et al. 2020

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Advances in immunotherapy have achieved remarkable clinical outcomes in tumors with low curability, but their effects are limited, and increasing evidence has implicated tumoral and non-tumoral components of the tumor microenvironment as critical mediators of cancer progression. At the same time, the clinical successes achieved with minimally invasive and optically-guided surgery and image-guided and ablative radiation strategies have been successfully implemented in clinical care. More effective, localized and safer treatments have fueled strong research interest in radioimmunotherapy, which has shown the potential immunomodulatory effects of ionizing radiation. However, increasingly more observations suggest that immunosuppressive changes, metabolic remodeling, and angiogenic responses in the local tumor microenvironment play a central role in tumor recurrence. In this review, we address challenges to identify responders vs. non-responders to the immune checkpoint blockade, discuss recent developments in combinations of immunotherapy and radiotherapy for clinical evaluation, and consider the clinical impact of immunosuppressive changes in the tumor microenvironment in the context of surgery and radiation. Since the therapy-induced modulation of the tumor microenvironment presents a multiplicity of forms, we propose that overcoming microenvironment related resistance can become clinically relevant and represents a novel strategy to optimize treatment immunogenicity and improve patient outcome.

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Radiation Therapy and the In Situ Vaccination Approach

Cited by 50 publications

References 89 publications

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies

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