{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:22:23Z","timestamp":1774459343655,"version":"3.50.1"},"reference-count":25,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"13","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2003,7,1]]},"abstract":"<jats:p>Purpose: To maintain interferon gamma (IFN\u03b3) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study.<\/jats:p><jats:p>Patients and Methods: Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng\/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU\/m<jats:sup>2<\/jats:sup>. Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12.<\/jats:p><jats:p>Results: Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng\/kg rhIL-12 plus 3 MU\/m<jats:sup>2<\/jats:sup>IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFN\u03b3 and IFN\u03b3-inducible protein-10 production by rhIL-12 and led to a three-fold expansion of natural killer cells. There was one major clinical response (partial response) as well as two pathologic responses; all occurred in melanoma patients. Stable disease for three to six cycles was only observed at or above the MTD in melanoma and renal cell cancer patients.<\/jats:p><jats:p>Conclusion: The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12\u2013responsive malignancies.<\/jats:p>","DOI":"10.1200\/jco.2003.12.119","type":"journal-article","created":{"date-parts":[[2003,6,30]],"date-time":"2003-06-30T19:58:12Z","timestamp":1057003092000},"page":"2564-2573","source":"Crossref","is-referenced-by-count":126,"title":["Phase I Trial of Concurrent Twice-Weekly Recombinant Human Interleukin-12 Plus Low-Dose IL-2 in Patients With Melanoma or Renal Cell Carcinoma"],"prefix":"10.1200","volume":"21","author":[{"given":"Jared A.","family":"Gollob","sequence":"first","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Korina G.","family":"Veenstra","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Parker","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James W.","family":"Mier","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David F.","family":"McDermott","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Clancy","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Tutin","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry","family":"Koon","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael B.","family":"Atkins","sequence":"additional","affiliation":[{"name":"From the Division of Hematology\/Oncology and the Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"233","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.13.040195.001343"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.178.4.1223"},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Nastala CL, Edington HD, McKinney TG, et al: Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 153:1697,1994\u20131706,","DOI":"10.4049\/jimmunol.153.4.1697"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5343.1623"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80585-3"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200110128"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/87.8.581"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1999.17.7.2105"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1994.03510360033032"},{"key":"R11","unstructured":"Atkins M, Robertson M, Gordon M, et al: Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 3:409,1997\u2013417,"},{"key":"R12","unstructured":"Gollob JA, Mier JW, Veenstra K, et al: Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: Ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res 6:1678,2000\u20131692,"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/88.1.38"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.15.3477"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1097\/00002371-200101000-00011"},{"key":"R16","unstructured":"Smith KA: Rational interleukin-2 therapy. Cancer J Sci Am 3:S137,1997\u2013S140,"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.10.3146"},{"key":"R18","doi-asserted-by":"crossref","unstructured":"Mehrotra PT, Donnelly RP, Wong S, et al: Production of IL-10 by human natural killer cells stimulated with IL-2 and\/or IL-12. J Immunol 160:2637,1998\u20132644,","DOI":"10.4049\/jimmunol.160.6.2637"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200206140-00007"},{"key":"R20","doi-asserted-by":"crossref","unstructured":"Ostensen ME, Thiele DL, Lipsky PE: Tumor necrosis factor-alpha enhances cytolytic activity of human natural killer cells. J Immunol 138:4185,1987\u20134191,","DOI":"10.4049\/jimmunol.138.12.4185"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.3.779"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.3.910"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3861"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.3.902.415k23_902_908"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.1.67"},{"key":"R26","unstructured":"Pluda JM, Wyvill K, Little R, et al: A pilot\/dose-finding study of interleukin 12 (IL-12) administered to patients with AIDS-associated Kaposi\u2019s sarcoma (KS). Proc Am Soc Clin Oncol 18:547a,1999,"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2003.12.119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T16:35:59Z","timestamp":1682526959000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2003.12.119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,7,1]]},"references-count":25,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2003,7,1]]}},"alternative-id":["10.1200\/JCO.2003.12.119"],"URL":"https:\/\/doi.org\/10.1200\/jco.2003.12.119","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,7,1]]}}}