Increasing Anti-Tumor Response by Localized High Dose Radiation

Sci Transl Med 6 June 2012: 

Vol. 4, Issue 137, p. 137ra74 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003649

• RESEARCH ARTICLE

TUMOR RADIOTHERAPY

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

1. Steven K. Seung¹,²,*, 
2. Brendan D. Curti¹,³,*,†, 
3. Marka Crittenden¹,², 
4. Edwin Walker¹, 
5. Todd Coffey³,
6. Janet C. Siebert⁴, 
7. William Miller¹, 
8. Roxanne Payne³, 
9. Lyn Glenn³, 
10. Alexandru Bageac⁵ and
11. Walter J. Urba¹,³

+Author Affiliations

1. ¹Earle A. Chiles Research Institute, Portland, OR 97213, USA.
2. ²The Oregon Clinic, Portland, OR 97213, USA.
3. ³Providence Cancer Center, Portland, OR 97213, USA.
4. ⁴CytoAnalytics, Denver, CO 80217, USA.
5. ⁵Providence Portland Medical Center, Portland, OR 97213, USA.

+Author Notes

• ↵* These authors contributed equally to this work.

1. ↵†To whom correspondence should be addressed. E-mail: Brendan.Curti@Providence.org

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.

• Copyright © 2012, American Association for the Advancement of Science

Citation: S. K. Seung, B. D. Curti, M. Crittenden, E. Walker, T. Coffey, J. C. Siebert, W. Miller, R. Payne, L. Glenn, A. Bageac, W. J. Urba, Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2—Tumor and Immunological Responses. Sci. Transl. Med. 4,137ra74 

http://stm.sciencemag.org/content/4/137/137ra74.full