Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2—Tumor and Immunological Responses

Abstract

Preclinical models suggest that focal high-dose radiation can make tumors more immunogenic. We performed a pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) to assess safety and tumor response rate and perform exploratory immune monitoring studies. Patients with metastatic melanoma or renal cell carcinoma (RCC) who had received no previous medical therapy for metastatic disease were eligible. Patients received one, two, or three doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting IL-2. IL-2 (600,000 IU per kilogram by means of intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Patients with regressing disease received up to six IL-2 cycles. Twelve patients were included in the intent-to-treat analysis, and 11 completed treatment per the study design. Response Evaluation Criteria in Solid Tumors criteria were used to assess overall response in nonirradiated target lesions. Eight of 12 patients (66.6%) achieved a complete (CR) or partial response (PR) (1 CR and 7 PR). Six of the patients with PR on computed tomography had a CR by positron emission tomography imaging. Five of seven (71.4%) patients with melanoma had a PR or CR, and three of five (60%) with RCC had a PR. Immune monitoring showed a statistically significantly greater frequency of proliferating CD4(+) T cells with an early activated effector memory phenotype (CD3(+)CD4(+)Ki67(+)CD25(+)FoxP3(-)CCR7(-)CD45RA(-)CD27(+)CD28(+/-)) in the peripheral blood of responding patients. SBRT and IL-2 can be administered safely. Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data, we believe that the combination and investigation of CD4(+) effector memory T cells as a predictor of response warrant further study.

Radiobiology of stereotactic body radiation therapy (SBRT)

“…Recent examples of objective clinical responses achieved by the combination of radiotherapy and immunotherapy support the view that both treatments can act synergistically. 79,80 The combination of radiation therapy and immunotherapy is under active preclinical and clinical investigation. In the USA, more than 50 clinical trials are currently testing the addition of radiation therapy to various immunotherapies.…”

An Uncommon Presentation for Cardiac Melanoma

“…4,46 Hiniker et al 47 hypothesized that radiationinduced apoptosis may stimulate an antitumor immune response 48 in the setting of anti-CTLA-4 treatment. They employed radiotherapy combined with immunotherapy as a noninvasive in vivo tumor vaccine strategy in a patient with metastatic melanoma involving the liver.…”

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

“…75 In addition, there are several reports of a potent abscopal effect when ipilimumab and IL-2 were used after localized radiotherapy, suggesting that combinations of immunotherapy and standard radiation treatment might also be a possible therapeutic strategy. 76,77 Another immuno therapeutic strategy demonstrating promise is the use of an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor for the treatment of melanoma, and results of a randomized phase III clinical trial are awaited. 78 Another approach is to use T cells expressing modified T-cell receptors capable of recognizing tumour-associated antigens while providing T-cell activation signals upon antigen recognition.…”