Journal of Immunotherapy 10:355-362 © 1991 Raven Press, Ltd., New York
Phase I Evaluation of Recombinant Tumor Necrosis Factor Given in Combination With Recombinant Interferon-Gamma John W. Smith II, *Walter J. Urba, Jeffrey W. Clark, Dan L. Longo, tMargi Farrell, Stephen P. Creekmore, Kevin C. Conlon, ^Howard Jaffe, and Ronald G. Steis Biological Response Modifiers Program, Clinical Research Branch, and ^Program Resources, Incorporated/DynCorp, National Cancer Institute—FCRDC, and ^Frederick Memorial Hospital, Frederick, Maryland; and tGenentech, Incorporated, South San Francisco, California, U.S.A.
Summary: In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-7) and tumor necrosis factor-alpha (TNF-a), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients were given an intramuscular (i.m.) injection of IFN-7, followed 5 min later by an i.m. injection of TNF-a, each agent in different sites, every other day for ten doses over 20 days. Patients received 10, 50, or 100 |j,g/m2 of each agent throughout the treatment course. No dose modifications were made. Patients suffering serious toxicity had therapy stopped and were considered to be offstudy. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 |xg/m2 of both agents developed serious toxicity (one fever >105°F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 jig/m2 of IFN-7 plus 50 |xg/m2 of TNF-a. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells. Key Words: Tumor necrosis factor—Interferon-gamma—Phase I trial—Combination immunotherapy—Outpatient immunotherapy.
The combination of recombinant human tumor necrosis factor-alpha (rTNF-a) and recombinant human interferon-gamma (rIFN-7) has demonstrated additive or synergistic antitumor effects in
many preclinical experiments. Enhanced antiproliferative effects of the combination have been observed in several murine and human tumor cell lines (1-3). Additive antineoplastic effects of the two agents combined were observed against fresh tumor biopsies grown in the human tumor colony assay system (4). Using both rTNF-a and rIFN-7, increased therapeutic efficacy was noted in vivo in the treatment of experimental and spontaneous me-
Received March 5, 1991; accepted April 4, 1991. Address correspondence and reprint requests to Dr. J. W. Smith II at NCI-FCRDC, Suite 3, 501 West Seventh Street, Frederick, MD 21701, U.S.A.
355
J. W. SMITH
356
tastases, as well as established subcutaneous tumors from a syngeneic murine melanoma (5,6). The combination of the two agents also resulted in enhanced antitumor effects against established human tumor xenografts derived from primary breast, colon, and ovarian cancers (7,8). The mechanism of the additive or synergistic effects has not been definitively established. rIFN-7 upregulates TNF receptors, and early reports postulated that this explained the observed synergism (9-11); however, more recent studies suggest that this is not a major mechanism of synergy (12,13). Other plausible explanations include the cooperative inhibitory effect of these two cytokines on c-myc expression (14,15) or the interaction of rIFN-7 with rTNF-a to produce DNA fragmentation (16). Additive effects of the two agents in vivo could also be due to modulation of the immune system, such as enhancing human leukocyte antigen (HLA) classes I and II antigen expression on tumor cells (17) or augmenting macrophage-mediated cytotoxicity (5,18). With the purpose of evaluating the toxicity and immunomodulating effects of rTNF-a given in combination with rIFN-7, we conducted a phase I study in patients with solid tumors. We investigated a chronic outpatient treatment regimen, and chose to give rTNF-a i.m. due to the dose-limiting inflammation at the injection site observed when rTNF-a was given subcutaneously (19). We demonstrated that the combination could be administered safely in the outpatient setting over 3 weeks. The maximum tolerated dose (MTD) was 100 j^g/m2 rIFN-7 and 50 jxg/m2 rTNF-a, given i.m. every other day. No toxicities were observed that had not been noted with either agent used alone in previous trials.
IIETAL. weeks after treatment with nitrosoureas or mitomycin); (d) adequate hematologic, renal, hepatic, pulmonary, and metabolic functions [white blood cell (WBC) count 3=3,000/mm3, granulocytes > 1,500/ mm3, platelets >100,000/mm3, prothrombin time (PT)
Phase I Evaluation of Recombinant Tumor Necrosis Factor Given in Combination With Recombinant Interferon-Gamma John W. Smith II, *Walter J. Urba, Jeffrey W. Clark, Dan L. Longo, tMargi Farrell, Stephen P. Creekmore, Kevin C. Conlon, ^Howard Jaffe, and Ronald G. Steis Biological Response Modifiers Program, Clinical Research Branch, and ^Program Resources, Incorporated/DynCorp, National Cancer Institute—FCRDC, and ^Frederick Memorial Hospital, Frederick, Maryland; and tGenentech, Incorporated, South San Francisco, California, U.S.A.
Summary: In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-7) and tumor necrosis factor-alpha (TNF-a), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients were given an intramuscular (i.m.) injection of IFN-7, followed 5 min later by an i.m. injection of TNF-a, each agent in different sites, every other day for ten doses over 20 days. Patients received 10, 50, or 100 |j,g/m2 of each agent throughout the treatment course. No dose modifications were made. Patients suffering serious toxicity had therapy stopped and were considered to be offstudy. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 |xg/m2 of both agents developed serious toxicity (one fever >105°F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 jig/m2 of IFN-7 plus 50 |xg/m2 of TNF-a. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells. Key Words: Tumor necrosis factor—Interferon-gamma—Phase I trial—Combination immunotherapy—Outpatient immunotherapy.
The combination of recombinant human tumor necrosis factor-alpha (rTNF-a) and recombinant human interferon-gamma (rIFN-7) has demonstrated additive or synergistic antitumor effects in
many preclinical experiments. Enhanced antiproliferative effects of the combination have been observed in several murine and human tumor cell lines (1-3). Additive antineoplastic effects of the two agents combined were observed against fresh tumor biopsies grown in the human tumor colony assay system (4). Using both rTNF-a and rIFN-7, increased therapeutic efficacy was noted in vivo in the treatment of experimental and spontaneous me-
Received March 5, 1991; accepted April 4, 1991. Address correspondence and reprint requests to Dr. J. W. Smith II at NCI-FCRDC, Suite 3, 501 West Seventh Street, Frederick, MD 21701, U.S.A.
355
J. W. SMITH
356
tastases, as well as established subcutaneous tumors from a syngeneic murine melanoma (5,6). The combination of the two agents also resulted in enhanced antitumor effects against established human tumor xenografts derived from primary breast, colon, and ovarian cancers (7,8). The mechanism of the additive or synergistic effects has not been definitively established. rIFN-7 upregulates TNF receptors, and early reports postulated that this explained the observed synergism (9-11); however, more recent studies suggest that this is not a major mechanism of synergy (12,13). Other plausible explanations include the cooperative inhibitory effect of these two cytokines on c-myc expression (14,15) or the interaction of rIFN-7 with rTNF-a to produce DNA fragmentation (16). Additive effects of the two agents in vivo could also be due to modulation of the immune system, such as enhancing human leukocyte antigen (HLA) classes I and II antigen expression on tumor cells (17) or augmenting macrophage-mediated cytotoxicity (5,18). With the purpose of evaluating the toxicity and immunomodulating effects of rTNF-a given in combination with rIFN-7, we conducted a phase I study in patients with solid tumors. We investigated a chronic outpatient treatment regimen, and chose to give rTNF-a i.m. due to the dose-limiting inflammation at the injection site observed when rTNF-a was given subcutaneously (19). We demonstrated that the combination could be administered safely in the outpatient setting over 3 weeks. The maximum tolerated dose (MTD) was 100 j^g/m2 rIFN-7 and 50 jxg/m2 rTNF-a, given i.m. every other day. No toxicities were observed that had not been noted with either agent used alone in previous trials.
IIETAL. weeks after treatment with nitrosoureas or mitomycin); (d) adequate hematologic, renal, hepatic, pulmonary, and metabolic functions [white blood cell (WBC) count 3=3,000/mm3, granulocytes > 1,500/ mm3, platelets >100,000/mm3, prothrombin time (PT)
