ATM inhibition augments type I interferon response and antitumor T-cell immunity when combined with radiation therapy in murine tumor models.

Background: Radiation therapy (RT) elicits DNA double-strand breaks, resulting in tumor cytotoxicity and a type I interferon (IFN) response via stimulator of interferon genes (STING) activation. We investigated whether combining RT with an ataxia-telangiectasia mutated inhibitor promoted these effects and amplified tumor immunity.

Methods: Mice-bearing syngeneic flank tumors (MOC2 head and neck squamous cell carcinoma or B78 melanoma) were treated with tumor-directed RT and oral administration of AZD0156.

Radiation Augments the Local Anti-Tumor Effect of Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models.

Introduction: Combining CpG oligodeoxynucleotides with anti-OX40 agonist antibody (CpG+OX40) is able to generate an effective vaccine in some tumor models, including the A20 lymphoma model. Immunologically "cold" tumors, which are typically less responsive to immunotherapy, are characterized by few tumor infiltrating lymphocytes (TILs), low mutation burden, and limited neoantigen expression. Radiation therapy (RT) can change the tumor microenvironment (TME) of an immunologically "cold" tumor.

Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy.

Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source.

Combination of Bempegaldesleukin and Anti-CTLA-4 Prevents Metastatic Dissemination After Primary Resection or Radiotherapy in a Preclinical Model of Non-Small Cell Lung Cancer.

Surgical resection or hypo-fractionated radiation therapy (RT) in early-stage non-small cell lung cancer (NSCLC) achieves local tumor control, but metastatic relapse remains a challenge. We hypothesized that immunotherapy with anti-CTLA-4 and bempegaldesleukin (BEMPEG; NKTR-214), a CD122-preferential IL2 pathway agonist, after primary tumor RT or resection would reduce metastases in a syngeneic murine NSCLC model. Mice bearing Lewis Lung Carcinoma (LLC) tumors were treated with combinations of BEMPEG, anti-CTLA-4, and primary tumor treatment (surgical resection or RT).

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial-Membrane-Coated Nanoparticles.

Neoantigens induced by random mutations and specific to an individual's cancer are the most important tumor antigens recognized by T cells. Among immunologically "cold" tumors, limited recognition of tumor neoantigens results in the absence of a de novo antitumor immune response. These "cold" tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs).