Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells

Abstract

Purpose Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab. Experimental Design SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to 5 treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. Maximum tolerated dose was determined with a 3+3 dose de-escalation design. Immune marker expression was assessed by flow cytometry. Results Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting ≥6 months). Clinical benefit was associated with increases in peripheral CD8+ T-cells; CD8+/CD4+ T-cell ratio; and proportion of CD8+ T-cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T-cells expressing ICOS, GITR, and 4-1BB. Conclusions Combining SABR and ipilimumab was safe with signs of efficacy; peripheral T-cell markers may predict clinical benefit; and systemic immune activation was greater after liver irradiation.

Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy

“…Clinical studies revealed that the recommended dose of ipilimumab in phased combination with chemotherapies was identified as 10 mg/kg and had a better treatment benefit in combination with chemotherapeutic agents, such as carboplatin, etoposide and paclitaxel in patients with lung cancer [94][95][96] and advance melanoma [97,98]. Moreover,combining radiotherapy and ipilimumab was feasible and well tolerated with limited toxicity for solid tumors [99]. The report showed that radiation with doses ranged from 45-61.2 Gy in patients with stage IIIA NSCLC after 3 cycles of neo-adjuvant chemotherapy including ipilimumab with the last two cycles was well tolerated with no observed grade≥3 toxicity including NSCLC [100].In patients with metastatic castrationresistant prostate cancer, the combination of ipilimumab with radiotherapy (8Gy/lesion, up to 3 lesions) showed synergistic antitumor activity with disease control and manageable adverse effects [101].In addition, the efficacy of ipilimumab with other immunotherapies was evaluated in a number of clinical trials.…”

Radio-immunotherapy and chemo-immunotherapy as a novel treatment paradigm in malignant pleural mesothelioma

“…We therefore established animal models of mesothelioma in mice to assess the interaction of radiation and the immune system using a non-ablative short course of hypofractionated radiation such as 15 Gy in 3 fractions (9,27). When this type of radiation is delivered to the primary tumor, tumorassociated antigens (Ag) are released from dead tumor cells and then processed by antigen presenting cells (APC) such as DCs.…”

“…Local radiation resulted in an increase of tumor-infiltrating T cells, while CTLA-4 blockade led to significant reduction of Tregs and increase of CTLs in both tumors. The abscopal effect was enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma (9).…”

“…Therefore, a large number of studies have focused on multimodality approaches for the treatment of this disease (3,4). Nowadays, combination of multimodality treatment with immunotherapy has been evaluated in pre-clinical studies and is entering clinical trials (5)(6)(7)(8)(9).…”

PD-L1 expression in lung cancer

“…To further explore the role of immunotherapy for SCLC, our department is conducting an investigator-initiated phase I study to assess the effects of pembrolizumab and radiation in extensive and limited stage disease (NCT02402920). The rationale behind such a treatment paradigm is that radiation releases antigens, providing greater immune system access to the array of somatic mutations inherent in this disease (18,19).…”