In SituTumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments

Abstract

Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment anti-tumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL-2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T cell response. Given the T cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared to combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T cell checkpoint blockade, with immediate implications for clinical evaluation.

Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group

“…However, if this strategy were to be validated, it could enable administration of this regimen of immunotherapy to those that would best benefit, and allow avoiding this somewhat toxic 5-month regimen (or using a different strategy) for those who might not benefit from this regimen. Enhancements to anti-GD2 mAb-based therapy, based on preclinical and early clinical data are being evaluated in efforts to improve its efficacy (22,25–27). Since we cannot be certain that the benefit in the immunotherapy group observed for patients with KIR-ligands present or for patients with KIR2DL2+/C1+/KIR3DL1+/Bw4+ will be applicable for newer generations of anti-GD2 immunotherapeutic regimens, further studies of KIR/KIR-ligand associations with outcome in subsequent trials of immunotherapeutic regimens for children with neuroblastoma will be needed to determine the potential clinical utility of these findings.…”

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

“…Several factors may in part explain these differences: cell autonomous effects resulting in greater suppression of downstream signaling, tumor-stroma crosstalk that is not recapitulated using standard in vitro culture approaches, or anti-tumor effects of ADCC in vivo (even within an immune compromised model). While the immunodeficient nude mouse is far from an ideal model for the study of antitumor immunity, these animals do produce NK cells (41) and have been used to study the role of ADCC using tumor-specific antibodies(42). We looked for tumor infiltrating immune cells by morphological analysis of H&E stained slides and CD45 IHC in cetuximab and control treated animals.…”

Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma

“…Others and we have demonstrated the cooperative interaction of combination treatment with radiation and immunotherapy in vivo . Many of these studies demonstrate that the timing and sequencing of radiation and immunotherapy may be critical for optimizing cooperative anti-tumor activity [11, 12]. Illustratively, in preclinical studies we recently demonstrated a cooperative interaction between RT and the antibody-dependent cell-mediated cytotoxicity (ADCC) response to tumor-specific monoclonal antibodies (mAb) in murine melanoma [11].…”

“…Many of these studies demonstrate that the timing and sequencing of radiation and immunotherapy may be critical for optimizing cooperative anti-tumor activity [11, 12]. Illustratively, in preclinical studies we recently demonstrated a cooperative interaction between RT and the antibody-dependent cell-mediated cytotoxicity (ADCC) response to tumor-specific monoclonal antibodies (mAb) in murine melanoma [11]. This effect was enhanced using a combination of RT and immunocytokine, a fusion of the tumor-specific antibody with IL2, resulting in elimination of 5-week established tumors in most mice and a memory T cell response.…”