Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy.

Patients with cancer and with preexisting active autoimmune diseases (ADs) have been excluded from immunotherapy clinical trials because of concerns for high susceptibility to the development of severe adverse events resulting from exacerbation of their preexisting ADs. However, a growing body of evidence indicates that immune-checkpoint inhibitors (ICIs) may be safe and effective in this patient population. However, baseline corticosteroids and other nonselective immunosuppressants appear to negatively impact drug efficacy, whereas retrospective and case report data suggest that use of specific immunosuppressants may not have the same consequences. Therefore, we propose here a two-step strategy. First, to lower the risk of compromising ICI efficacy before their initiation, nonselective immunosuppressants could be replaced by specific selective immunosuppressant drugs following a short rotation phase. Subsequently, combining ICI with the selective immunosuppressant could prevent exacerbation of the AD. For the most common active ADs encountered in the context of cancer, we propose specific algorithms to optimize ICI therapy. These preventive strategies go beyond current practices and recommendations, and should be practiced in ICI-specialized clinics, as these require multidisciplinary teams with extensive knowledge in the field of clinical immunology and oncology. In addition, we challenge the exclusion from ICI therapy for patients with cancer and active ADs and propose the implementation of an international registry to study such novel strategies in a prospective fashion.

Recent skin self-examination and doctor visits in relation to melanoma risk and tumour depth.

BACKGROUND: Little is known about the potential benefit of skin self-examination for melanoma prevention and early detection. OBJECTIVES: To determine whether skin self-examination is associated with reduced melanoma risk, self-detection of tumours, and reduced risk of deeper melanomas. METHODS: We used data from a population-based case-control study (423 cases, 678 controls) to assess recent skin self-examination in relation to self-detection, melanoma risk and tumour depth ( ≤1 mm; > 1 mm). Logistic regression was used to estimate odds ratios (ORs) and confidence intervals (CIs) for associations of interest. RESULTS: Skin self-examination conducted 1-11 times during a recent year was associated with a possible decrease in melanoma risk (OR 0·74; 95% CI 0·54-1·02). Melanoma risk was decreased for those who conducted skin self-examination and saw a doctor (OR 0·52; 95% CI 0·30-0·90). Among cases, those who examined their skin were twice as likely to self-detect the melanoma (OR 2·23; 95% CI 1·47-3·38), but self-detection was not associated with shallower tumours. Tumour depth was reduced for those who conducted skin self-examination 1-11 times during a recent year (OR 0·39; 95% CI 0·18-0·81), but was not influenced by seeing a doctor, or by conducting skin self-examination and seeing a doctor. CONCLUSIONS: Risk of a deeper tumour and possibly risk of melanoma were reduced by skin self-examination 1-11 times annually. Melanoma risk was markedly reduced by skin self-examination coupled with a doctor visit. We cannot, however, exclude the possibility that our findings reflect bias or confounding. Additional studies are needed to elucidate the potential benefits of skin self-examination for melanoma prevention and early detection.

Interferon Alfa-2b Adjuvant Therapy of High-Risk Resected Cutaneous Melanoma: The Eastern Cooperative Oncology Group Trial EST 1684.

PURPOSE: Interferon alfa-2b (IFN alpha-2b) exhibits antitumor activity in metastatic melanoma and on this basis has been evaluated as an adjuvant therapy following surgery for deep primary (T4) or regionally metastatic (N1) melanoma. METHODS: A randomized controlled study of IFN alpha-2b (Schering-Plough, Kenilworth, NJ) administered at maximum-tolerated doses of 20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three times per week subcutaneously (SC) for 48 weeks versus observation, was conducted by the Eastern Cooperative Oncology Group (ECOG) in 287 patients. RESULTS: A significant prolongation of relapse-free survival (P = .0023, one-sided) and prolongation of overall survival (P = .0237, one-sided) was observed with IFN alpha-2b therapy in this trial, which is now mature with a median follow-up time of 6.9 years. The impact of treatment on relapse rate is most pronounced early during the treatment interval. The overall benefit of treatment in this trial was analyzed stratified by tumor burden and the presence or absence of microscopic nonpalpable and palpable regional lymph node metastasis. The benefit of therapy with IFN alpha-2b was greatest among node-positive strata. Toxicity of IFN alpha-2b required dose modification in the majority of patients, but treatment at > or = 80% of the scheduled dose was feasible in the majority of patients through the IV phase of treatment, and for more than 3 months of SC maintenance therapy. Discontinuation of treatment due to toxicity was infrequent after the fourth month of therapy. CONCLUSION: IFN alpha-2b prolongs the relapse-free interval and overall survival of high-risk resected melanoma patients. The increment in median disease-free survival (from 1 to 1.7 years) and overall survival (from 2.8 to 3.8 years) that results from this therapy is associated with a 42% improvement in the fraction of patients who are continuously disease-free after treatment with IFN (from 26% to 37%) in comparison to observation. IFN alpha-2b is the first agent to show a significant benefit in relapse-free and overall survival of high-risk melanoma patients in a randomized controlled trial.

Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma.

BACKGROUND: Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin(®)) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS: In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA-paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS: No significant difference in OS was noted between patients in the DHA-paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA-paclitaxel. CONCLUSIONS: DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted.

Cardiovascular adverse events are associated with usage of immune checkpoint inhibitors in real-world clinical data across the United States.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause life-threatening cardiovascular adverse events (CVAEs) that may not be attributed to therapy. The outcomes of clinical trials may underestimate treatment-related adverse events due to restrictive eligibility, limited sample size, and failure to anticipate selected toxicities. We evaluated the incidence and clinical determinants of CVAEs in real-world population on ICI therapy. PATIENTS AND METHODS: Among 2 687 301 patients diagnosed with cancer from 2011 to 2018, 16 574 received ICIs for any cancer. Patients in the ICI and non-ICI cohorts were matched in a 1 : 1 ratio according to age, sex, National Cancer Institute comorbidity score, and primary cancer. The non-ICI cohort was stratified into patients who received chemotherapy (N = 2875) or targeted agents (N = 4611). All CVAEs, non-cardiac immune-related adverse events occurring after treatment initiation, baseline comorbidities, and treatment details were identified and analyzed using diagnosis and billing codes. RESULTS: Median age was 61 and 65 years in the ICI and non-ICI cohorts, respectively (P < 0.001). ICI patients were predominantly male (P < 0.001). Lung cancer (43.1%), melanoma (30.4%), and renal cell carcinoma (9.9%) were the most common cancer types. CVAE diagnoses in our dataset by incidence proportion (ICI cohort) were stroke (4.6%), heart failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction (0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%). Anti-cytotoxic T-lymphocyte-associated protein 4 increased the risk of heart failure [versus anti-programmed cell death protein 1; hazard ratio (HR), 1.9; 95% confidence interval (CI) 1.27-2.84] and stroke (HR, 1.7; 95% CI 1.3-2.22). Pneumonitis was associated with heart failure (HR, 2.61; 95% CI 1.23-5.52) and encephalitis with conduction disorders (HR, 4.35; 95% CI 1.6-11.87) in patients on ICIs. Advanced age, primary cancer, nephritis, and anti-cytotoxic T-lymphocyte-associated protein 4 therapy were commonly associated with CVAEs in the adjusted Cox proportional hazards model. CONCLUSIONS: Our findings underscore the importance of risk stratification and cardiovascular monitoring for patients on ICI therapy.

Early recovery of aggressive cytotoxic cells and improved immune resurgence with post-transplant immunotherapy for multiple myeloma.

A phase I/II trial evaluated early administration and dose escalation of interleukin (IL)-2 with granulocyte macrophage colony stimulating factor (GM-CSF) post-transplant. Following melphalan (200 mg/m(2)) and an autologous transplant, IL-2 was initiated (day 0) and continued for 4 weeks. GM-CSF (250 mcg/m(2)/day) began on day 5. Fifteen of 19 patients completed therapy. No treatment-related deaths occurred. IL-2 (1 x 10(6) IU/m(2)/day) was not tolerated in two of six patients due to > or =grade 3 fatigue/diarrhea (n=1) or supraventricular tachycardia (n=1). The maximum tolerated dose of IL-2 was 6 x 10(5) IU/m(2)/day; this dose was well tolerated by 11 of 13 patients. Neutrophil and platelet engraftment occurred on day 13 (median; range 10-17 days) and day 13 (median; range 0-74 days), respectively. When compared to control patients, there was a marked increase in the number of CD3+ T cells (P=0.005), CD4+ T cells (P=0.01), CD8+ T cells (P=0.001) and CD4+CD25+Treg cells (P=0.015) post-transplant. Cytotoxicity directed against myeloma cells was markedly increased when compared to control patients (P=0.017). This unique trial design using early administration of IL-2 with GM-CSF during the period of lymphodepletion, demonstrated a marked increase in the number and function of early cytotoxic effector T cells, without suppression of engraftment.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Plasminogen activator and its inhibitor in cancer patients treated with tumor necrosis factor.

BACKGROUND: We noted the presence of plasma fibrin degradation products in patients treated with recombinant human tumor necrosis factor (TNF) in a phase I trial. PURPOSE: To further define this observation, we investigated the effects of TNF on the fibrinolytic system in patients entered in the same trial. METHODS: In the 14 patients studied, fibrinolytic parameters were measured by analyzing blood samples for tissue plasminogen activator and inhibitor at 0, 1, 2, 4, 6, and 18-24 hours after initiation of TNF treatment. We used a chromogenic substrate method to determine activity of plasminogen activator and its inhibitor and an enzyme-linked immunosorbent assay (ELISA) to determine levels of antigen (tissue-type plasminogen activator). Molecular weight was determined by zymographic assay. RESULTS: TNF treatment was associated with tissue-type plasminogen activator induction within 1 hour of TNF initiation. The plasminogen activator produced was consistent with tissue-type plasminogen activator derived from endothelium as evidenced by molecular weight analysis and ELISA. Moreover, induction of plasminogen activator inhibitor occurred following the release of tissue-type plasminogen activator, and our data suggest a dose-response effect for TNF. At high doses (i.e., 200 and 240 micrograms/m2), there was a more rapid and prolonged release of plasminogen activator inhibitor, which had an inverse relationship with the level of antigenic tissue-type plasminogen activator. Zymographic analysis showed urokinase-type plasminogen activator activity in 13 of 14 patients. In three patients, simultaneous measurements of white blood cells and tissue-type plasminogen activator revealed a temporal association between the TNF-associated rapid granulocytopenia at 30 minutes after TNF initiation and release of tissue-type plasminogen activator antigen. CONCLUSIONS: The results suggest a positive association between TNF and rapid induction of plasminogen activator activity that is consistent with an endothelial product. It is possible that, at high doses, TNF may interact directly with vascular endothelium, leading to rapid and prolonged production of plasminogen activator inhibitor. There was a dose-response effect between TNF and release of tissue-type plasminogen activator. The release of tissue-type plasminogen activator was preceded by granulocytopenia, which may indicate an association between a proposed TNF-induced granulocyte-endothelial interaction in vivo and release of tissue-type plasminogen activator. IMPLICATIONS: These findings demonstrating the effects of TNF on the fibrinolytic system can be analyzed further in experimental systems to determine the implications for use of this agent as a biological response modifier in cancer therapy.

Urinary excretion of interferon, albumin, and beta 2-microglobulin during interferon treatment.

Serum and urinary levels of albumin, beta 2-microglobulin, and interferon were determined in ten patients undergoing interferon therapy. The pharmacokinetics during a phase I trial of interferon administration intramuscularly is presented. Only trace amounts of interferon activity are found in the urine, even during peak serum interferon activity. Serum beta 2-microglobulin levels increased after interferon treatment, especially at the higher dosing levels. Urinary excretion of beta 2-microglobulin increased due to the relatively low affinity of the transport system. Saturation, competition, or inhibition of the absorption process for beta 2-microglobulin was not attained. Measurement of the urinary albumin/urinary beta 2-microglobulin ratio reveals no glomerular or tubular lesion, and we conclude that interferon therapy does not result in a clinically significant nephrotoxicity.

Expression of Fas(APO-1/CD95) in tumor-infiltrating and peripheral blood lymphocytes in patients with renal cell carcinoma.

The functional expression of Fas-ligand on tumor cells reported in a variety of neoplasms has been proposed by several groups as a mechanism of tumor escape from immunological detection. To better support this hypothesis, we have evaluated and quantified for the first time the presence of the Fas(CD95)-R molecule on tumor-infiltrating lymphocytes and on matched peripheral blood lymphocytes (PBLs) of renal cell cancer patients. By two-color flow cytometry we have detected a significant increase in the Fas(CD95)-R expression on tumor-infiltrating lymphocytes compared with matched patient and normal volunteer PBLs. We also observed a decreased expression of the Fas(CD95)-R expression on PBLs from renal cell cancer patients compared with normal healthy controls. The Fas(CD95)-R expression was observed predominantly on the CD4+ subset in all three groups. These different distributions of the Fas(CD95)-R molecule support the hypothesis that the Fas(CD95)-R/Fas(CD95)-L pathway and tumor microenvironment play a major role in the modulation of T-cell function and differentiation to either memory and activation or apoptosis.

T-cell receptor zeta-chain expression on tumor-infiltrating lymphocytes from renal cell carcinoma.

Loss of the T-cell receptor-associated zeta chain in tumor-infiltrating lymphocytes (TILs) has been proposed as one mechanism of acquired immunosuppression in cancer patients. Recent reports suggest that zeta-chain loss may be related to contaminating monocyte/macrophage protease activity. Using flow cytometry and Western blot analysis, we have confirmed the expression of zeta chain in matched peripheral blood mononuclear cells and TILs from eight patients with primary renal cell carcinoma, when the cells were exposed to sufficient quantity of protease inhibitors. A small decrease in zeta-chain expression was found in three TIL samples. The loss of zeta-chain expression that was noted by others may be related to differences in laboratory method, and the small changes we have noted are unlikely to be sufficient in explaining the immunosuppression of TILs.

Dysplastic nevi in association with multiple primary melanoma.

Risk factors for multiple primary cutaneous melanoma were evaluated in a case-control study. Eight cases of multiple primary melanoma were matched on sex, age, and education to 24 first primary melanoma controls. Risk factors examined in the analysis included pigmentary characteristics, history of sun exposure, and nevi. The importance of histologically dysplastic nevi (DN) and clinically atypical nevi was of particular interest. Single-factor conditional logistic regression analysis showed that first primary melanoma patients with histological DN are at increased risk for a second primary (odds ratio, 6.2; 95% confidence interval, 1.2-33.4). Patients with two or more clinically atypical nevi also have elevated risk for a second primary (odds ratio, 8.8; 95% confidence interval, 1.0-80.7). Two-factor logistic models were used to evaluate the effect of histological DN while controlling singly for all other variables as potential confounders. Odds ratios for the association of histological DN varied from 6.1 to 10.4 when adjusting singly for pigmentary and sun exposure variables. In the two-factor model that included histological and clinical DN, both variables retained marginally significant statistical association with multiple primary melanoma. These results suggest that DN is a marker of increased risk for multiple primary melanoma and suggest that melanoma patients with evidence of DN should be followed closely for the development of additional primaries.

A randomized study of low and high doses of leukocyte alpha-interferon in metastatic renal cell carcinoma: the American Cancer Society collaborative trial.

A prospective randomized trial of low versus high doses of human leukocyte alpha-interferon (1 X 10(6) units/day for 28 days versus 10 X 10(6) units/day for 28 days) was carried out in 30 patients with metastatic renal cell carcinoma, to test the tolerance and relative antitumor effects of these interferon doses. Both doses were tolerated well, and responses to the human leukocyte alpha-interferon were observed overall in seven individuals, including complete, partial, and minimal tumor regressions. Six of the seven responses occurred in patients who received the high dosage, and three of these responses were major responses. While not statistically significant, this result suggested a dose-response relationship. One minimal response was observed in a patient treated at low dosage. Nine individuals who were stable after 1 month of therapy at low dosage were randomized to a further month of therapy at low or high dosage, during which one of four at high dosage had a partial response, and none of five at low dosage manifested response. Regression of pulmonary disease in one individual was delayed, occurring 3 months after therapy at the high dose and enduring for a period of 28 months. Major objective responses in other patients were of 4 and 15 months duration. Human leukocyte alpha-interferon is an active agent in renal cell carcinoma at the dosage of 10 million units daily. No relationship of toxicity to response was evident in this trial. Optimum dosage and duration of treatment have yet to be established.

Phase I studies with trimetrexate: clinical pharmacology, analytical methodology, and pharmacokinetics.

Twenty-two patients with advanced solid tumors were treated with a quinazoline folate antagonist, trimetrexate, to determine the toxicity spectrum, the maximal tolerated dose, and the pharmacokinetics of the drug. Negligible toxicity was seen with single doses of 10-70 mg/m2 given as a 1-h infusion. Single doses of 120 mg/m2 infused over 1 h caused moderate to grade 4 toxicity in five of nine patients treated. Two patients who had no toxicity at this level were escalated to a dose of 213 mg/m2 with mild to moderate toxicity. The primary dose-limiting toxicity was myelosuppression. Moderate transaminase elevations, rash, anorexia, nausea and vomiting, and mucositis were occasionally seen. Although there was variation in dose tolerance to this drug, with selected patients able to tolerate higher doses, we consider 120 mg/m2 every 2 weeks to be the maximal tolerated dose, and the recommended Phase II starting dose. Trimetrexate plasma concentration-time curves were best described as biphasic (N = 9) or triphasic (N = 5) in form. The half-life of the terminal elimination-phase was 16.4 h. The mean residence time was 17.8 h. The volume of distribution of the plasma compartment and the volume of distribution at steady-state were 0.17 and 0.62 liter/kg, respectively. Plasma clearance was 53 ml/min. Plasma concentrations as determined by dihydrofolate reductase enzyme inhibition assay and high-performance liquid chromatography were initially identical, but diverged at later times. Divergences were seen also in urinary recovery as determined by the two methods. Both results suggest the appearance of metabolite(s) of trimetrexate which can inhibit dihydrofolate reductase. Measurable objective solid tumor responses were not seen in this Phase I study, although three patients with colon cancer had stable disease lasting 18, 26, and 26 weeks, respectively.

Immunological effects of treatment with sequential administration of recombinant interferon gamma and alpha in patients with metastatic renal cell carcinoma during a phase I trial.

Many anticancer mechanisms of the interferons have been proposed but none have been associated with clinical response to date. The biological activities of the interferons in vivo have included effects upon the natural killer cell, T- and B-lymphocytes, and macrophages. This report details a prospective study of the immunological effects on peripheral blood mononuclear cells of sequentially administered recombinant (r) interferon (IFN) gamma and rIFN alpha in 28 patients with metastatic renal cell carcinoma. Natural killer cell activity, T-cell phenotype (CD4, CD8, CD56, CD16, CD4/HLA-DR, CD8/HLA-DR, CD56/HLA-DR) and 2',5'-oligoadenylate synthetase were measured prior to therapy, during therapy, and following completion of treatment. Statistical analysis of all parameters was performed for the entire group, by individual patient, by dosage, by time, and by clinical response. An overall significant depression in natural killer cell activity and in the percentage of circulating CD56, CD16, and CD8+ cells were noted. Significant increases in 2',5'-oligoadenylate synthetase and in the percentage of circulating CD4 cells were also noted. Although an association between the magnitude of change in percentage of CD16+ cells and 2',5'-oligoadenylate synthetase and dosage of rIFN gamma and rIFN alpha, respectively, was observed, optimal biological dose of this sequence of rIFNs could not be determined due to the limited number of patients. A decrease in the percentage of circulating CD8+ cells was observed among patients with objective clinical response (partial and complete). Sequentially administered rIFN gamma and rIFN alpha can modulate immunological parameters in vivo in patients with metastatic renal cell carcinoma. A fall in percentage of circulating CD8+ cell is associated with response and suggests that this sequence of rIFN alpha and rIFN gamma might influence T-cell mediated antitumor activity.

Interferons in the treatment of human cancer.

The interferons are the best known of biologic antineoplastic agents. Progress with the clinical application of interferons to cancer has been slow and complicated by the need for attention to a new spectrum of therapeutic and toxic effects manifest by the interferons. This summary of current phase I and II trial results with the interferons establishes their clinical potential. The maximally tolerated dosages of the most common species of interferon alpha produced in eukaryotic cells as well as by recombinant DNA technology in bacteria are now described in a variety of different disease states. "Naturally" produced eukaryotic as well as bacterially synthesized interferons have a similar, wide range of biologic effects in vitro and in vivo. Antiviral, antiproliferative, immunologic, and enzymologic functions of the interferons relevant to antineoplastic functions are under study. Knowledge of these mechanisms should improve the clinical results obtained in human cancer. Species and subspecies differences in the activity of interferons may lead to selective use of the pure interferon subspecies, alone or in combination. The use of the interferons and other antineoplastic biologics, such as antibody or chemotherapy, are subsequent goals that are now on the horizon.

A phase IA trial of sequential administration recombinant DNA-produced interferons: combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma.

This study investigated the effects of sequentially administered recombinant interferon gamma (rIFN gamma) and recombinant interferon alfa (rIFN alpha) in 36 patients with metastatic renal cell carcinoma (RCC). rIFN alpha was subcutaneously administered daily for 70 days at dosages that varied (2.5, 5, 10, and 20 x 10(6) U/m2) across four cohorts of patients. Within each cohort of patients receiving a given dose of rIFN alpha, three subsets of patients received either 30, 300, or 1,000 micrograms/m2 rIFN gamma. rIFN gamma was administered intravenously for 5 days every third week, 6 hours prior to administration of rIFN alpha. Dose-limiting toxicity (DLT) included constitutional symptoms, leukopenia, nephrotic syndrome with acute renal failure, hypotension associated with death, and congestive heart failure. DLT was related more often to the rIFN alpha dose level than to rIFN gamma dose level. Maximum-tolerated dose (MTD) was 10 x 10(6) U/m2 rIFN alpha and 1,000 micrograms/m2 rIFN gamma. Six patients failed to complete a minimum of 21 days of therapy due to toxicity or rapid progression of disease. Clinical responses were seen in eight of 30 assessable patients. Two patients experienced complete remission and have remained in complete remission 20+ and 22+ months. An additional six patients have shown partial responses for 4 to 18+ months. One patient in partial remission continues to show slow regression of pulmonary and liver lesions off therapy with rIFNs. Clinical responses have remained durable for patients with complete remissions and patients with partial remissions. The results of this study suggest that toxicities associated with combination rIFN therapy can be reduced by administering these agents sequentially as opposed to simultaneously.

In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.

Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.