Robert K. Oldham

Constant-Infusion Recombinant Interleukin-2 in Adoptive Immunotherapy of Advanced Cancer

Adoptive immunotherapy involving bolus-dose recombinant interleukin-2 (rIL-2) has been reported to induce tumor regression in some patients with cancer, but has been associated with severe fluid retention and cardiopulmonary stress. In an effort to preserve the efficacy but reduce the toxicity of this treatment, we used escalating doses of rIL-2 as a constant infusion rather than as a bolus dose. Forty-eight patients with advanced cancer received rIL-2 as a 24-hour infusion in five-day cycles separated by five-day periods of rest and leukapheresis. Eight patients were removed from the study before receiving cells activated in vitro. In the 40 who could be evaluated for their response, there were 13 partial responses (32.5 percent) and 2 minor responses. Partial responses were observed in Hodgkins disease (one of one), non-Hodgkins lymphoma (one of one), lung cancer (one of five), ovarian cancer (one of one), parotid cancer (one of two), renal cancer (three of six), and melanoma (five of ten). Responses were associated with a good performance status, a base-line lymphocyte count above 1400 per cubic millimeter, and an rIL-2-induced lymphocyte count of at least 6000. Optimal lymphocytosis required a priming dose of rIL-2 of 3 X 10(6) U per square meter of body-surface area per day, and 15 of 28 patients receiving this priming dose responded to treatment. A weight gain of more than 10 percent of total body weight (five patients) and dyspnea at rest (six patients) were unusual events restricted to patients with poorer pretreatment performance. We conclude that the administration of rIL-2 as a constant infusion may preserve the antineoplastic activity of adoptive immunotherapy while increasing the safety and comfort of patients.

Treatment of advanced non-Hodgkin's lymphoma with recombinant leukocyte A interferon

We report the results of a trial of recombinant leukocyte A interferon in previously treated patients with non-Hodgkins lymphoma who were no longer responsive to chemotherapy. Patients received recombinant leukocyte A interferon (50 X 10(6) U per square meter of body-surface area) by intramuscular injection three times weekly for three months or longer. Forty-five patients were enrolled in the study, and 37 were evaluated for a response. Thirteen of 24 (54 per cent) evaluable patients with low-histologic-grade non-Hodgkins lymphoma had objective responses (nine partial responses and four histologically confirmed complete responses). Two of six (33 per cent) with intermediate-grade lymphoma responded (one partially and one completely), and one of seven (14 per cent) with high-grade lymphoma had a partial response. The median duration of responses was eight months. Four of the five complete responders have continued to receive maintenance interferon and have been in complete remission for 3, 7, 9, and 12 months, respectively; one had a recurrence at a site of previous disease seven months after interferon had been stopped. Side effects were noted in most patients. All 16 responders had been heavily pretreated with combination chemotherapy, including doxorubicin in 8 of the 16. These results suggest that recombinant leukocyte A interferon may be an effective new therapy for some patients with low- and intermediate-grade non-Hodgkins lymphoma.

Recombinant Leukocyte A Interferon: An Active Agent in Advanced Cutaneous T-Cell Lymphomas

High-dose recombinant leukocyte A interferon (50 X 10(6) U/m2 body surface area, intramuscularly, three times weekly) was tested in a clinical trial involving patients with advanced cutaneous T-cell lymphomas to determine its effectiveness and toxicity. All 20 patients had advanced stages of disease refractory to two or more standard therapies. Objective partial remissions lasting 3 months to more than 25 months (median, 5 months) were documented in 9 patients. The major dose-limiting toxicity was a severe influenza-like syndrome with malaise, anorexia, depression, weight loss, and decreased performance status; this effect was reversible after dose reductions in all patients and did not recur with re-escalation of doses in 10 patients. This interferon preparation is highly effective in the treatment of advanced refractory cutaneous T-cell lymphomas, and new schedules to reduce toxicity and achieve complete responses, combined treatment with chemotherapy or serotherapy, and its use in earlier stages of disease should be investigated.

Monoclonal antibody therapy of malignant melanoma: in vivo localization in cutaneous metastasis after intravenous administration.

The murine antimelanoma monoclonal antibody, 9.2.27, was administered intravenously to eight patients with metastatic malignant melanoma. Biopsies of metastatic nodules clearly demonstrate the selective localization of this antibody on the melanoma cell surface with a dose-response relationship to the quantity of administered antibody. The antibody infusions were clinically well tolerated and the pharmacokinetics of the antibody and the antiglobulin responses are described. This study indicates that murine monoclonal antibodies have potential as selective targeting agents in the design of future therapeutic trials using monoclonal antibodies or conjugates thereof in the treatment of cancer.

Monoclonal Antibodies in Cancer Therapy: 25 Years of Progress

In 1983, it was apparent that a major problem with current modalities of cancer treatment was the lack of specificity for the cancer cell. It was predicted that a major advancement in treatment of cancer would be the development of a class of agents that would have a greater degree of specificity for the tumor cell. Based on many animal studies and the treatment of fewer than 100 patients, it was evident in 1983 that monoclonal antibodies would be that major advance. The first patient treated in the United States with monoclonal antibody therapy was a patient with non-Hodgkin’s lymphoma. Nadler et al described the treatment using a murine monoclonal antibody designated AB 89. Although treatment was not successful in inducing a significant clinical response, it did represent the first proof of principle in humans that a monoclonal antibody could induce transient decreases in the number of circulating tumor cells, induce circulating dead cells, and form complexes with circulating antigen, all with minimal toxicity to the patient. Antibody could be detected on the surface of circulating lymphoma cells, and free antigen in the serum decreased with each infusion of antibody. After two courses of milligram doses of AB 89, a final and third course with 1.5 g of antibody was administered during a 6-hour period. A marked reduction in circulating antigen was noted, but these studies suggested to the authors that the quantity of circulating antigen was too great to effectively deliver AB 89 to the patient’s tumor cells in a therapeutically effective manner. In the Journal of Clinical Oncology review article cited earlier, evidence was reviewed from animal tumor models that clearly demonstrated both specificity and therapeutic efficacy with little serious toxicity. Whereas passive serotherapy of human cancer had shown little success, it was apparent in the earlier review that monoclonal antibodies could be used in the treatment of leukemia and lymphoma. In 1983, a review of the literature revealed approximately 10 published studies and one in-press article of therapeutic trials of monoclonal antibody therapy in humans. All of these studies used murine monoclonal antibodies and were phase I/II studies. Most were in leukemia or lymphoma, but the earliest solid tumor studies were also underway in melanoma and GI cancer. By 1983, the pioneers in monoclonal antibody research believed that a new era of cancer therapy had begun, and for the first time, true specific and targeted therapy was underway using hybridoma technology to produce monoclonal antibodies with exquisite specificity. It was also apparent, based on animal model studies, that monoclonal antibodies could be a vehicle to bring immunoconjugate therapy to the clinic by conjugating monoclonal antibodies to drugs, toxins, and radioisotopes using the specificity of the monoclonal antibody to carry enhanced killing capacity directly to the tumor cells. Thus, the era of monoclonal antibody therapy, as well as immunoconjugate therapy, had begun. Although there was much excitement (and skepticism) about this new treatment modality (the use of a form of biologic therapy with great specificity in patients with advanced cancer) there were also problems and limitations. As presented in Table 1, there were clinical toxicities with murine monoclonal antibodies, most of which were secondary to the interaction with the target antigen. However, the major limitation was their immunogenicity. Murine proteins are highly immunogenic, and it was soon found that only a few infusions of these foreign proteins could be given to patients with cancer because of the development of human antimouse antibody. Another problem quickly became apparent, in that some of the antigens on cancer cell surfaces modulated off the surface and into the circulation when antibody attached. Modulation could also cause internalization of the complex. It was recognized that this could represent a therapeutic advantage by using the antibody as carrier to internalize the toxic component of an immunoconjugate, potentially making it more therapeutically active. In 1983, few specific antigens found only in cancer cells had been identified, and there was much debate about the specificity of these antigens. Many of the antigens to which monoclonal antibodies were made were embryonic antigens or shared antigens found on cancer cells and some normal cells. Therefore, although the specificity of the antibody was exquisite for the antigen, the specificity for the antibody or immunoconjugate for cancer was not absolute. One fairly clear exception occurred early in the 1980s when Levy et al developed monoclonal antibodies to the idiotype of B-lymphoma cells. The first patient given this anti-idiotypic antibody had a complete response to therapy, and his lymphoma went into a sustained remission that lasted for years. As a direct result of these early studies with anti-idiotypic antibodies, there is now a series of idiotype vaccines that are in phase III trials in patients with low-grade follicular lymphomas. These antiidiotype vaccines will likely be the first truly custom-tailored, personalized anticancer vaccines to be approved for therapeutic use. JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 11 APRIL 1

Small cell lung cancer: Complete remission and improved survival☆

Thirty-two patients with limited-stage small cell lung cancer were treated with combined supervoltage radiotherapy and a combination of cyclophosphamide, doxorubicin and vincristine chemotherapy. The goal of obtaining a complete remission, the necessary step which precedes improved survival, was successful in 26 of 27 of completely re-evaluated patients. Fiberoptic bronchoscopy was useful in substantiating complete remission status. Seventeen of the 32 patients remain alive from 8+ to 28+ months (median 16+ months). Ten patients are alive and relapse-free from 12+ to 28+ months (median 19+ months). Transient granulocytopenia (mean nadir 650 cells/mm3) during induction therapy and the associated risk of infection were the most serious toxicities encountered. This therapy produces complete remission on roentgenography and bronchoscopy, symtomatic improvement and improved survival in the majority of patients with limited-stage small cell lung cancer. A portion of these patients may have their disease eradicated.

Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a National Biotherapy Study Group trial.

We conducted a multicenter, phase II trial of continuous-infusion recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells. Patients had advanced cancer, measurable disease, and a good performance level. Treatment included a 5-day continuous infusion of 18 x 10(6) IU/m2/d of rIL-2 followed by 1 day of rest, 4 days of leukapheresis to collect cells for in vitro augmentation of cellular cytotoxicity, and 5 more days of rIL-2 infusion with reinfusion of LAK cells for 3 successive days. Therapy was repeated after 2 weeks. There were 117 patients enrolled: 63% were males, with a median age of 51 years. Eighty-two percent were managed in oncology units, and 18% were in intensive care units. Six patients died within 1 month of initiating therapy. In renal cell carcinoma, the response rate was one of 31 patients (3%), with a median survival of 10.7 months. In melanoma, the response rate was four of 33 patients (12%), with a median survival of 6.1 months. For all other histologies, response rate was three of 53 patients (5%), with a median survival of 7.4 months. All responders were asymptomatic when therapy was initiated. This trial confirms the feasibility of administering continuous rIL-2 and LAK cells outside the intensive care unit environment. Antitumor activity in melanoma was similar to that seen in multicenter trials of bolus rIL-2 and LAK cells. Activity in renal cell cancer was disappointing.

The Unrecognized Extragonadal Germ Cell Cancer Syndrome

Within 3 years we saw 12 patients diagnosed initially as having poorly differentiated or undifferentiated carcinomas who, we believe, actually had extragonadal germinal cancers. Serum levels of the beta subunit of human chorionic gonadotropin (beta-HCG) or alpha-fetoprotein were useful in suggesting and supporting the diagnosis: Levels of one or the other were elevated in six of 10 patients in whom they were measured but levels of both, in only one patient. Staining of histologic specimens for beta-HCG or alpha-fetoprotein showed intracellular localization of one of these markers in the cancer cells of all four patients studied. All patients responded to therapy (11 treated with chemotherapy with or without radiotherapy, one with excision and radiotherapy only), with complete remissions in seven of 12. Two of the patients who had a complete remission have experienced relapse, and five have continued in disease-free remission from more than 8 to more than 56 months. Histologically atypical extragonadal germ cell neoplasms may be commoner than previously supposed. Physicians should consider this treatable and potentially curable cancer in selected patients having poorly differentiated or undifferentiated carcinomas.

Continuous interleukin‐2 and tumor‐infiltrating lymphocytes as treatment of advanced melanoma. A national biotherapy study group trial

Melanoma metastases were harvested from 82 patients for the purpose of growing and expanding tumor‐infiltrating lymphocytes (TIL). Tumor tissue cell suspensions were incubated with interleukin‐2 (IL‐2), followed by repeated exposure to tumor antigen with or without OKT3 monoclonal antibody (MoAb). Initial growth success was achieved in 56 of 82 cultures (72%). Efforts were made to expand 26 of these 56 cultures for therapeutic TIL; 23 of 26 early cultures (88%) were successfully expanded for in vivo therapy. It took a mean of 78.5 ± 25.4 days to grow sufficient TIL for treatment. Therapy included cyclophosphamide (1 g/m2) on day 1, followed by a 96‐hour continuous infusion of IL‐2 (18 × 106 IU/m2/d) on days 2 to 5, and approximately 1011 (mean 1.49 ± 0.93 × 1011) TIL on day 2. Patients who responded received monthly IL‐2 as a 96‐hour infusion. Median patient age was 45 years of age. Sixty‐seven percent of the patients were men. Performance status was 0 to 1 in 77% of patients. Thirty‐four percent of the patients had liver metastases. The usual IL‐2 toxicities were seen. Response rate for 21 patients was 24% (95% confidence interval, 10% to 49%). One complete response was achieved with cells 98% CD4+; four partial responses were achieved with cells 80%, 94%, 98%, and 98% CD8+, respectively. Four of eight patients who received TIL, which had never been stimulated with OKT3, had tumor response. The authors conclude that a treatment plan for IL‐2/TIL is technically difficult, costly, and effective for only a minority of patients. Overall, clinical results are not clearly superior to those obtained with other IL‐2 regimens.

Phase II trial of recombinant leukocyte A interferon in patients with advanced chronic lymphocytic leukemia

Recombinant leukocyte A interferon is a highly purified single molecular species of alpha-interferon prepared by recombinant DNA methods. In 1982, a phase II trial to evaluate the efficacy of recombinant leukocyte A interferon for patients with previously treated chronic lymphocytic leukemia was begun, and 19 patients were entered in this study. Patients received one of two dose schedules depending on their pretreatment platelet counts. Those with platelet counts greater than 100,000/mm3 received 50 X 10(6) units/m2 intramuscularly three times weekly, with dose reductions to 25 X 10(6) units/m2 and 5 X 10(6) units/m2 for unacceptable toxicity. Those with platelet counts less than 100,000/mm3 received 5 X 10(6) units/m2 intramuscularly three times weekly. Toxicity was dose-dependent and included fever, chills, fatigue, anorexia, myalgias, headache, leukopenia, and thrombocytopenia. Response was evaluable in all but one of the patients entered in this study. Two of the 12 patients treated with 50 X 10(6) units/m2 had a partial response, three had no response, and seven had progressive disease. Of the six patients starting at 5 X 10(6) units/m2 in whom response was evaluable, two had no response and four had progressive disease. Five patients with progressive disease (three at 50 X 10(6) units/m2 and two at 5 X 10(6) units/m2) had an acceleration of disease while receiving recombinant leukocyte A interferon. It is concluded that the dose and schedule of recombinant leukocyte A interferon therapy tested in this study are not effective in previously treated patients with advanced chronic lymphocytic leukemia.