Current clinical trials testing the combination of immunotherapy with radiotherapy

Kang, Josephine; Demaria, Sandra; Formenti, Silvia C.

doi:10.1186/s40425-016-0156-7

Cited by 332 publications

(284 citation statements)

References 93 publications

(98 reference statements)

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“…10 Combination of radiation and various immunotherapies have been under investigation in the clinic. 11 Among immune intervention therapies, interleukin-12 (IL-12) is considered as the most potent cytokine in triggering antitumor immune responses. 12,13 IL-12 is critical in the activation of innate immunity, including antigen-presenting activity of DCs, and subsequent activation of T-helper 1 cell (Th1) immunity, and in promoting the killing function of cytotoxic T lymphocytes and natural killer cells.…”

Section: Introductionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8+ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

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Section: Introductionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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“…Platinum is used widely in chemotherapeutics of NSCLC [69,70]. Platinum-based chemotherapy and targeted therapies are milestones in lung cancer treatment [71,72].…”

Section: Lncrnas Radiochemotherapy In Nsclcmentioning

confidence: 99%

Diagnostic and Prognostic Potential of Circulating Long Non-Coding RNAs in Non Small Cell Lung Cancer

Peng

Wang

Shan

et al. 2018

Cell Physiol Biochem

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Lung cancer is the leading cause of cancer-related mortality worldwide. Approximately 80% of lung cancer cases are non–small cell lung carcinoma (NSCLC). However current diagnostic and therapeutic modalities against NSCLC are ineffective due to incomplete understanding of molecular pathogenesis of NSCLC. Emerging evidence shows that long non-coding RNAs (lncRNAs) can function as biomarkers for diagnosis and prognosis. LncRNAs can control transcription, translation, and protein function via diverse mechanisms although they lack the protein coding potential. LncRNAs have attracted intense investigations on their roles in cancer. Mounting evidence indicates that lncRNAs are promising biomarkers in diagnosis and prognosis for NSCLC, especially their presence in body fluids. Herein we will review recent advances in the research that explores the diagnostic and prognostic potentials of lncRNAs in NSCLC. We will also discuss emerging evidence that suggested lncRNAs as therapeutic targets in NSCLC.

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“…Radiation affects the immune system in many ways including release of neoantigens, upregulation of PD-L1 on tumor cells, recruitment of T cells to the tumor bed and neutralization of the immune-suppressive effects of the tumor microenvironment. Over 60% of patients with NSCLC require radiotherapy at least once during their course of treatment, and radiotherapy used in combination with immune checkpoint blockade has shown potential in preclinical and early clinical studies [3,6,7,18]. A Phase II trial of consolidation pembrolizumab initiated 1-2 months after concurrent chemoradiation demonstrated safety of such treatment [19].…”

mentioning

confidence: 99%

“…By activating the immune system to recognize and eliminate cancer, immune checkpoint blockade has the potential to elicit durable responses and augment survival outcomes for a subset of patients [1,2]. In addition, the ability of radiotherapy to induce an immunogenic response and neutralize the immune-suppressive effects of the tumor microenvironment, uniquely positions it as a synergistic tool at the center of emerging multimodal therapies utilizing immune checkpoint blockade [3][4][5][6][7].Immune checkpoint inhibitors of the PD-1/PD-L1 pathway have emerged as a promising new therapeutic strategy [8][9][10][11]. These agents have produced durable clinical responses and antitumor activity in Phase I trials, leading to subsequent randomized Phase II and III trials that demonstrated significant improvements in overall survival when compared with cytotoxic chemotherapy alone [12][13][14][15][16].…”

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confidence: 99%

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Can radiotherapy potentiate the effectiveness of immune checkpoint inhibitors in lung cancer?

et al. 2017

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Systemic therapy including platinum-based chemotherapy and targeted therapy has been a mainstay of treatment for the majority of patients with metastatic non-small-cell lung cancer (NSCLC). Recent breakthroughs in immune checkpoint blockade, along with a deeper understanding of tumor immune biology, have led to a paradigm shift in the standard of care for cancer treatment. By activating the immune system to recognize and eliminate cancer, immune checkpoint blockade has the potential to elicit durable responses and augment survival outcomes for a subset of patients [1,2]. In addition, the ability of radiotherapy to induce an immunogenic response and neutralize the immune-suppressive effects of the tumor microenvironment, uniquely positions it as a synergistic tool at the center of emerging multimodal therapies utilizing immune checkpoint blockade [3][4][5][6][7].Immune checkpoint inhibitors of the PD-1/PD-L1 pathway have emerged as a promising new therapeutic strategy [8][9][10][11]. These agents have produced durable clinical responses and antitumor activity in Phase I trials, leading to subsequent randomized Phase II and III trials that demonstrated significant improvements in overall survival when compared with cytotoxic chemotherapy alone [12][13][14][15][16]. These studies have established PD-1/PD-L1 pathway blockade as a powerful new line of therapy for patients with advanced NSCLC following progression after platinum-based therapy [9,11]. Despite unprecedented improvements in clinical outcomes, less than 20% of patients respond to anti-PD-1/PD-L1 agents, necessitating strategies that explore combined treatment modalities in order to extend the benefits of immune checkpoint blockade to a broader patient population. The Phase II KEYNOTE-021 trial (NCT02039674), for example, evaluated the treatment of pembrolizumab in combination with pemetrexed and carboplatin and found significantly prolonged progression-free survival (median 13.0 vs 8.9 months; 6-month survival 92% for both arms) for patients with previously untreated metastatic nonsquamous NSCLC [17]. This trial, as well as the KEYNOTE-024 trial (NCT02142738), has served to bring PD-1 inhibition into the front-line setting for NSCLC [13].Radiation has become known for its abscopal effect in lung cancer. There are many compelling reasons to combine radiotherapy with checkpoint inhibition in the treatment of NSCLC. Radiation affects the immune system in many ways including release of neoantigens, upregulation of PD-L1 on tumor cells, recruitment of T cells to the tumor bed and neutralization of the immune-suppressive effects of the tumor microenvironment. Over 60% of patients with NSCLC require radiotherapy at least once during their course of treatment, and radiotherapy used in combination with immune checkpoint blockade has shown potential in preclinical and early clinical studies [3,6,7,18]. A Phase II trial of consolidation pembrolizumab initiated 1-2 months after concurrent chemoradiation demonstrated safety of such treatment [19]. In fact, in May 2017...

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Current clinical trials testing the combination of immunotherapy with radiotherapy

Cited by 332 publications

References 93 publications

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Diagnostic and Prognostic Potential of Circulating Long Non-Coding RNAs in Non Small Cell Lung Cancer

Can radiotherapy potentiate the effectiveness of immune checkpoint inhibitors in lung cancer?

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