Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy

Sharabi, Andrew B.; Lim, Michael; DeWeese, Theodore L.; Drake, Charles G.

doi:10.1016/s1470-2045(15)00007-8

Cited by 726 publications

(567 citation statements)

References 77 publications

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“…The abscopal effect is facilitated by the immune system and has been found anecdotally to mediate long-term, durable clinical responses. The synergistic interaction between radiotherapy and immunotherapy is thought to be due to immune stimulation by radiation-induced pro-inflammatory protein production and increased exposure of immune cells to cancer specific antigens that are released following radiotherapy-induced cancer cell death 13–16 . We hypothesized that NPs could be used to improve treatment response to immunotherapy and to induce the abscopal effect by capturing tumor-derived protein antigens (TDPA) released during radiotherapy and transporting them to antigen presenting cells (APCs), thereby promoting cancer immunity (Figure 1) 17–22 .…”

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confidence: 99%

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

et al. 2017

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Immunotherapy holds tremendous promise for improving cancer treatment1. Administering radiotherapy with immunotherapy has been shown to improve immune responses and can elicit an “abscopal effect”2. Unfortunately, response rates for this strategy remain low3. Herein, we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NPs formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent upon NP surface properties. We showed that AC-NPs deliver tumor specific proteins to antigen-presenting cells and significantly improve the efficacy of αPD-1 treatment using the B16F10 melanoma model, generating up to 20% cure rate as compared to 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+/Treg and CD8+/Treg ratios. Our work presents a novel strategy for improving cancer immunotherapy with nanotechnology.

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Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

et al. 2017

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“…43 At the same time, emerging evidences indicated that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells by recruiting infiltrated lymphocytes in an IFNg-dependent manner, and fractionated radiotherapy delivered in combination with anti PD-1 or anti PD-L1 mAbs generated efficacious CD8 C T-cell responses that improved local tumor control, long-term survival, and protection against tumor re-challenge. 44,45 Although we showed that the PD-1-disrupted LMP2A-CTLs conferred enhanced cytotoxicity to the EBV-positive gastric cancer cell line in vitro, in the xenograft model of EBVaGC, we did not observe augmented tumor regression following treatment of PD-1 disrupted LMP2A-CTL. The adoptive cell therapy showed therapeutic effect only when combined with low-dose radiotherapy (2Gy), and the PD-1-disrupted LMP2A-CTLs showed maximum efficacy.…”

Section: E1249558-10mentioning

confidence: 69%

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

Zou

Chen

et al. 2016

OncoImmunology

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The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1 pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC. These studies reveal possibility of generating PD-1-disrupted CTL by CRISPR-Cas9 system and demonstrate enhanced immune response of these PD-1-disrupted CTLs to the EBV-LMP2A antigen and superior cytotoxicity to the EBV-positive gastric cancer cell. In addition, when combined with low-dose radiotherapy, these PD-1-disrupted CTLs mediated an impressive antitumor effect in a xenograft mouse model of EBVaGC. Taken together, these studies illustrate PD-1/PD-L1-mediated immune tolerance of EBVaGC and provide a new strategy for targeting immune checkpoints to break the tolerance for the T cell-based adoptive therapy.

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“…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%

“…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].…”

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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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Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy

Cited by 726 publications

References 77 publications

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

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

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