Radiofrequency Ablation Combined with KS-IL2 Immunocytokine (EMD 273066) Results in an Enhanced Antitumor Effect against Murine Colon Adenocarcinoma

Johnson, Erik E.; Yamane, Brett; Buhtoiarov, Ilia N.; Lum, Hillary D.; Rakhmilevich, Alexander L.; Mahvi, David M.; Gillies, Stephen D.; Sondel, Paul M.

doi:10.1158/1078-0432.ccr-09-0110

Cited by 43 publications

(35 citation statements)

References 48 publications

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“…Besides PD-L1 and PD-1, CTLA-4 has been shown to inhibit thermal ablation-induced antitumor activities (4, 30, 31). Besides immune inhibitory pathways, it has been shown that various cytokines that are used to enhance T cell homeostasis and T cell immune responses also increase the antitumor efficacy of RFA (32, 33). Thus future combination therapy with RFA and various immune modulators can be explored in the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

PD-1 Blockade Boosts Radiofrequency Ablation–Elicited Adaptive Immune Responses against Tumor

Shi

Chen

et al. 2016

Clinical Cancer Research

239

209

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Purpose Radiofrequency ablation (RFA) has been shown to elicit tumor-specific T cell immune responses but is not sufficient to prevent cancer progression. Here we investigated immune suppressive mechanisms limiting the efficacy of RFA. Experimental design We performed a retrospective case-controlled study on patients with synchronous colorectal cancer liver metastases who had received primary tumor resection with or without pre-operative RFA for liver metastases. Tumor infiltrating T cells and tumoral PD-L1 expression in human colorectal cancer tissues were analyzed by immunohistochemistry. T cell immune responses and PD-1/PD-L1 expression were also characterized in a RFA mouse model. In addition, the combined effect of RAF and PD-1 blockade was evaluated in the mouse RFA model. Results We found that RFA treatment of liver metastases increased not only T cell infiltration but also PD-L1 expression in primary human colorectal tumors. Using mouse tumor models, we demonstrated that RFA treatment of one tumor initially enhanced a strong T cell-mediated immune response in tumor. Nevertheless, tumor quickly overcame the immune responses by inhibiting the function of CD8+ and CD4+T cells, driving a shift to higher Treg to Teff ratio, and up-regulating of PD-L1/PD-1 expression. Furthermore, we established that the combined therapy of RFA and anti-PD-1 antibodies significantly enhanced T cell immune responses, resulting in stronger antitumor immunity and prolonged survival. Conclusions The PD-L1/PD-1 axis plays a critical role in dampening RFA-induced antitumor immune responses. And this study provides a strong rationale for combining RFA and the PD-L1/PD-1 blockade in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

PD-1 Blockade Boosts Radiofrequency Ablation–Elicited Adaptive Immune Responses against Tumor

Shi

Chen

et al. 2016

Clinical Cancer Research

239

209

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“…This was confirmed in the clinical setting where both cell types were upregulated in the peripheral blood of patients as a result of L19-IL2 treatment (34). Johnson and colleagues (45) combined an alternative immunocytokine, KS-IL2, with radiofrequency ablation in a murine colon adenocarcinoma (CT26). The combination increased growth suppression, and a greater proportion of CD4 þ and CD8 þ cells was observed.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy Combined with the Immunocytokine L19-IL2 Provides Long-lasting Antitumor Effects

Zegers

Rekers

Quaden

et al. 2015

Clinical Cancer Research

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Purpose: Radiotherapy modifies the tumor microenvironment and causes the release of tumor antigens, which can enhance the effect of immunotherapy. L19 targets the extra domain B (ED-B) of fibronectin, a marker for tumor neoangiogenesis, and can be used as immunocytokine when coupled to IL2. We hypothesize that radiotherapy in combination with L19-IL2 provides an enhanced antitumor effect, which is dependent on ED-B expression.Experimental Design: Mice were injected with syngeneic C51 colon carcinoma, Lewis lung carcinoma (LLC), or 4T1 mammary carcinoma cells. Tumor growth delay, underlying immunologic parameters, and treatment toxicity were evaluated after singledose local tumor irradiation and systemic administration of L19-IL2 or equimolar controls.Results: ED-B expression was high, intermediate, and low for C51, LLC, and 4T1, respectively. The combination therapy showed (i) a long-lasting synergistic effect for the C51 model with 75% of tumors being cured, (ii) an additive effect for the LLC model, and (iii) no effect for the 4T1 model. The combination treatment resulted in a significantly increased cytotoxic (CD8 þ

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“…Ex vivo interferon (IFN) response assays were conducted as previously described (26). Splenocytes from B78 tumor-bearing animals were harvested on day 12 of indicated treatment and co-cultured with B16 cells for 5 days.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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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.

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Radiofrequency Ablation Combined with KS-IL2 Immunocytokine (EMD 273066) Results in an Enhanced Antitumor Effect against Murine Colon Adenocarcinoma

Cited by 43 publications

References 48 publications

PD-1 Blockade Boosts Radiofrequency Ablation–Elicited Adaptive Immune Responses against Tumor

PD-1 Blockade Boosts Radiofrequency Ablation–Elicited Adaptive Immune Responses against Tumor

Radiotherapy Combined with the Immunocytokine L19-IL2 Provides Long-lasting Antitumor Effects

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

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