Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity

Younes, A.; Barsoumian, Hampartsoum B.; Sezen, Duygu; Verma, Vivek; Patel, Roshal R.; Wasley, Mark; Hu, Yun; Dunn, Joe Dan; He, Kewen; Chen, Fan; Menon, Hari; Masrorpour, Fatemeh; Gu, Meidi; Yang, Liangpeng; Puebla-Osorio, Nahum; Cortez, María Angélica; Welsh, James W.

doi:10.1016/j.tranon.2020.100983

Cited by 21 publications

(12 citation statements)

References 45 publications

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“…Thus, an alternative maximization strategy for ISV should be incorporation of local therapeutic interventions that accelerate tumor antigen release. ISV could be combined with radiotherapy 47 , photodynamic therapy 48 , thermal ablation 49 , irreversible electroporation 37 , 50 , cryoablation 51 or the recently developed near-infrared photoimmunotherapy. As our previous results showed that ICD is induced by K3-SPG itself 21 , these additional interventions would synergize with K3-SPG.…”

Section: Discussionmentioning

confidence: 99%

In situ vaccination using unique TLR9 ligand K3-SPG induces long-lasting systemic immune response and synergizes with systemic and local immunotherapy

Okada

Takahashi

Yaku

et al. 2022

Sci Rep

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Although checkpoint inhibitors (CPIs) have changed the paradigm of cancer therapy, low response rates and serious systemic adverse events remain challenging. In situ vaccine (ISV), intratumoral injection of immunomodulators that stimulate innate immunity at the tumor site, allows for the development of vaccines in patients themselves. K3-SPG, a second-generation nanoparticulate Toll-like receptor 9 (TLR9) ligand consisting of K-type CpG oligodeoxynucleotide (ODN) wrapped with SPG (schizophyllan), integrates the best of conventional CpG ODNs, making it an ideal cancer immunotherapy adjuvant. Focusing on clinical feasibility for pancreaticobiliary and gastrointestinal cancers, we investigated the antitumor activity of K3-SPG-ISV in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). K3-SPG-ISV suppressed tumor growth more potently than K3-ISV or K3-SPG intravenous injections, prolonged survival, and enhanced the antitumor effect of CPIs. Notably, in PDAC model, K3-SPG-ISV alone induced systemic antitumor effect and immunological memory. ISV combination of K3-SPG and agonistic CD40 antibody further enhanced the antitumor effect. Our results imply that K3-SPG-based ISV can be applied as monotherapy or combined with CPIs to improve their response rate or, conversely, with CPI-free local immunotherapy to avoid CPI-related adverse events. In either strategy, the potency of K3-SPG-based ISV would provide the rationale for its clinical application to puncturable pancreaticobiliary and gastrointestinal malignancies.

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Section: Discussionmentioning

confidence: 99%

In situ vaccination using unique TLR9 ligand K3-SPG induces long-lasting systemic immune response and synergizes with systemic and local immunotherapy

Okada

Takahashi

Yaku

et al. 2022

Sci Rep

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“… 61 Radiotherapy can paradoxically promote tumor growth and invasion through the recruitment and repolarization of TAMs at the tumor site, limiting the efficacy of radiotherapy. 62 This can be highlighted by the use of liposomal clodronate to deplete macrophages before ionizing radiation. The effect on TAMs depends on the dosage used, whether low doses (below 1 Gy) or high doses (above 10 Gy).…”

Section: Trends In the Clinical Trials Of Combination Therapymentioning

confidence: 99%

Landscape and perspectives of macrophage -targeted cancer therapy in clinical trials

Wang

Yang

et al. 2022

Molecular Therapy - Oncolytics

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“…The highly expressed postradiation TGFβ cytokine is supposed to have an immunosuppressive function that could be targeted by inhibitors to evoke more effective SRT-induced T cell antitumor activity, as evidenced by the CD8+ cells increase and immunosuppressive T regulatory cells decrease in peripheral blood of SRT-treated patients affected by HCC and administered with a well-tolerated TGFβ-specific blockade (galunisertib) [96]. A toll-like receptor 9 agonist was also successfully tested in metastatic lung adenocarcinoma in mice in order to turn off the immunosuppressive effects of high radiation doses (12 Gy × 3 fractions) so as to clearly prevail tumoricidal ones [97]. High radiation doses combined with immunotherapies are able to break through the wall of radioresistance of some tumors, such as renal cell carcinoma, notoriously refractory to conventionally fractionated radiotherapy, and also improve systemic control by producing abscopal effects [98].…”

Section: High Dose Per Fraction Radiotherapy and Immunotherapy: The Most Recent Evidence For A Successful Cooperationmentioning

confidence: 99%

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

Ferini¹,

Valenti²,

Tripoli³

et al. 2021

Cancers

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Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the “oxygen-guided radiation therapy” (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT.

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Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity

Cited by 21 publications

References 45 publications

In situ vaccination using unique TLR9 ligand K3-SPG induces long-lasting systemic immune response and synergizes with systemic and local immunotherapy

In situ vaccination using unique TLR9 ligand K3-SPG induces long-lasting systemic immune response and synergizes with systemic and local immunotherapy

Landscape and perspectives of macrophage -targeted cancer therapy in clinical trials

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

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