Biomedical subjects

D E White

Publications and source records attributed to D E White.

At least 19 recordsLinked to original sources

PubMed1999

Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine.

Patients with metastatic melanoma were immunized with an immunodominant peptide derived from the gp100 melanoma-melanocyte differentiation Ag that was modified to increase binding to HLA-A+0201. A total of 10 of 11 patients who received the g209-2M peptide alone developed precursors reactive with the native g209 peptide, compared with only 5 of 16 patients who received g209-2M peptide plus IL-2 (p2 = 0.005). Peptide reactivity closely correlated with the recognition of HLA-A+0201 melanoma cells (p < 0. 001). The decrease in immune reactivity when peptide was administered with IL-2 appeared specific for the immunizing peptide, since reactivity to an influenza peptide resulting from prior exposure was not affected. Preexisting antitumor precursors did not decrease when peptide plus IL-2 was administered. The administration of GM-CSF or IL-12 also resulted in a decrease in circulating precursors compared with the administration of peptide alone, though not as great a decrease as that seen with IL-2. Immunization with peptide plus IL-2 did, however, appear to have clinical impact since 6 of the 16 patients (38%) that received peptide plus IL-2 had objective cancer regressions. It thus appeared possible that immunization with peptide plus IL-2 resulted in sequestering or apoptotic destruction of newly activated immune cells at the tumor site. These represent the first detailed studies of the impact of immunization with tumor peptides in conjunction with a variety of cytokines in patients with metastatic cancer.

Adult↗

PubMed1999

Brain metastasis after immunotherapy in patients with metastatic melanoma or renal cell cancer: is craniotomy indicated?

The purpose of this study was to evaluate the outcome of surgical treatment of brain metastasis in patients with metastatic melanoma or renal cell cancer after interleukin-2 (IL-2) therapy. A retrospective analysis was conducted at the Surgery Branch, National Cancer Institute. All patients with a diagnosis of metastatic melanoma or renal cell cancer who received IL-2 from January 1, 1985 to January 1, 1996 (n = 1385) were screened for the development of brain metastasis. Forty patients underwent surgical treatment of brain metastasis that developed after initiating IL-2 therapy. Thirty-six were rendered free of disease after resection of a single metastasis and were the focus of this study. Twenty-two of the 36 patients achieved a clinical response (10 complete responses and 12 partial responses) at extracranial sites of disease after IL-2-based immunotherapy and before the development of brain metastasis. The median disease-free interval in the brain after resection of a single metastasis was 21, 7, and 3 months for patients achieving a complete response, partial response, and no response (CR, PR, and NR) to IL-2 therapy, respectively. The median survival after craniotomy for these three groups of patients was 23, 17, and 7 months, respectively. The disease-free interval in the brain and the overall survival after craniotomy were significantly longer for patients achieving a CR to previous immunotherapy when compared with patients achieving a PR or NR. Of the 10 patients who had achieved a prior CR, 8 remained disease free in the brain at last follow-up, 6 remained alive beyond 1 year, and 3 > 4 years. Twenty-five patients experienced neurologic symptoms before craniotomy and all had complete resolution of their symptoms after surgery. Surgical treatment of single brain metastasis in patients with metastatic melanoma or renal cell cancer is indicated in carefully selected patients. The benefits of resection include palliation of symptoms and the potential for a prolonged disease-free interval in the brain.

Adult↗

PubMed1999

Interleukin-2 based immunotherapy for metastatic renal cell carcinoma with the kidney in place.

PURPOSE: We assessed morbidity, response and survival in patients with metastatic renal carcinoma treated with high dose intravenous interleukin-2 (IL-2) based immunotherapy with the primary renal tumor in place. MATERIALS AND METHODS: We retrospectively analyzed the records of patients with metastatic renal carcinoma and the primary kidney tumor in situ who were treated at the surgery branch of the National Cancer Institute. Of the patients 607 were treated with IL-2 based therapy. Patient age, sex, sites of extrarenal disease, morbidity, and response and survival rates were examined. RESULTS: From 1986 to 1996, 51 patients with the majority of disease at extrarenal sites were treated with the primary tumor in place. Treatment involved IL-2 based regimens, reflecting the evolution of immunotherapy at the National Institutes of Health. When evaluating only extrarenal sites, response was complete in 1 and partial in 2 of the 51 cases (6%). No responses were noted in the primary renal tumor. Three patients with responses at extrarenal sites underwent nephrectomy. The duration of response in these 3 cases was greater than 88, 11 and 4 months, respectively. Median survival in all 51 patients was 13 months (range 1 to 86). CONCLUSIONS: Select patients may be treated with IL-2 based immunotherapy with the primary renal tumors in place with morbidity. A randomized study is needed to assess the role of cytoreductive nephrectomy for treating metastatic renal cell carcinoma.

Adult↗

PubMed1999

Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b.

PURPOSE: The combination of chemotherapy with immunotherapeutic agents such as interleukin-2 and interferon alfa-2b has been reported to provide improved treatment results in patients with metastatic melanoma, compared with the use of chemotherapy alone. We have performed a prospective randomized trial in patients with metastatic melanoma, comparing treatment with chemotherapy to treatment with chemoimmunotherapy. PATIENTS AND METHODS: One hundred two patients with metastatic melanoma were prospectively randomized to receive chemotherapy composed of tamoxifen, cisplatin, and dacarbazine or this same chemotherapy followed by interferon alfa-2b and interleukin-2. Objective responses, survival, and toxicity in the two groups were evaluated at a median potential follow-up of 42 months. RESULTS: In 52 patients randomized to receive chemotherapy, there were 14 objective responses (27%), including four complete responses. In 50 patients randomized to receive chemoimmunotherapy, there were 22 objective responses (44%) (P2 = .071), including three complete responses. In both treatment groups, the duration of partial responses was often short, and there was a trend toward a survival advantage for patients receiving chemotherapy alone (P2 = .052; median survival of 15.8 months compared with 10.7 months). Treatment-related toxicities were greater in patients receiving chemoimmunotherapy. CONCLUSION: With the treatment regimens used in this study, the addition of immunotherapy to combination chemotherapy increased toxicity but did not increase survival. The use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized protocols showing the benefit of this treatment strategy.

Adolescent↗

PubMed1998

Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens.

BACKGROUND: The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations. METHODS: In phase I studies, 54 patients received escalating doses (between 10(7) and 10(11) plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed. RESULTS: Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients. CONCLUSIONS: High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens.

Adenoviridae↗

PubMed1998

Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer.

BACKGROUND: Administration of recombinant high dose interleukin-2 (IL-2) can mediate tumor regression in patients with metastatic melanoma and renal carcinoma. Significant trends in the safety of high dose IL-2 administration at a single institution over a 12-year study period were reviewed. METHODS: A consecutive series of 1241 metastatic cancer patients treated with intravenous bolus infusions of IL-2 (720,000 IU/kg every 8 hours) were evaluated for the incidence of specific treatment-related toxicities, the maximum number of administered IL-2 doses, and objective response rates. RESULTS: Significant decreases in the incidence of Grade 3 and/or Grade 4 toxicities were found when the initial group of 155 patients was compared with the final group: Grade 3/4 line sepsis (18% vs. 4%), Grade 3/4 diarrhea (92% vs. 12%), Grade 4 neuropsychiatric toxicity (19% vs. 8%), pulmonary intubations (12% vs. 3%), Grade 3/4 hypotension (81% vs. 31%), and Grade 4 cardiac ischemia (3% vs. 0%). No treatment-related deaths were noted in the final 809 patients. Laboratory abnormalities, such as increased creatinine, hyperbilirubinemia, and thrombocytopenia, were less severe, whereas percent weight gain remained stable over the 12-year period. The maximum number of administered IL-2 doses during the first cycle of therapy decreased from an initial median of 13 doses to 7 doses per first treatment cycle. No significant differences in overall and ongoing complete response rates to high dose bolus IL-2 were observed for melanoma patients (two-tailed P value = 0.40 and 1.0, respectively), or renal carcinoma patients (two-tailed P value = 0.92 and 0.89, respectively) over the study period. CONCLUSIONS: Progressive reduction in morbidity and mortality was found with the systemic administration of high dose IL-2-based therapies over the 12-year study period. The improvement in safety most likely reflects the development of strategies to screen eligible patients, optimize therapeutic conditions, and judiciously terminate dosing when significant toxicities are noted. Despite these interventions, the overall and ongoing complete response rates for melanoma and renal carcinoma have not shown significant compromise. These trends suggest that high dose IL-2 can be safely administered to metastatic cancer patients under the current treatment guidelines and result in durable responses in a small subset of patients.

Adolescent↗

PubMed1998

Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.

The cloning of the genes encoding cancer antigens has opened new possibilities for the treatment of patients with cancer. In this study, immunodominant peptides from the gp100 melanoma-associated antigen were identified, and a synthetic peptide, designed to increase binding to HLA-A2 molecules, was used as a cancer vaccine to treat patients with metastatic melanoma. On the basis of immunologic assays, 91% of patients could be successfully immunized with this synthetic peptide, and 13 of 31 patients (42%) receiving the peptide vaccine plus IL-2 had objective cancer responses, and four additional patients had mixed or minor responses. Synthetic peptide vaccines based on the genes encoding cancer antigens hold promise for the development of novel cancer immunotherapies.

Adult↗

PubMed1998

Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response.

OBJECTIVE: To determine the durability of complete responses in patients with metastatic melanoma or renal cancer treated with high-dose bolus interleukin-2 (IL-2) as well as the factors associated with the development of a complete response and the antigens mediating clinical responses. METHODS: A consecutive series of 409 patients with either metastatic melanoma or renal cancer who were treated with high-dose bolus IL-2 in the Surgery Branch, National Cancer Institute, between September 1985 and November 1996 have been analyzed with a median potential follow-up of 7.1 years. All patients were treated with 720,000 IU/kg administered by 15-minute intravenous infusions every 8 hours for up to 5 days as clinically tolerated per cycle. Two cycles constituted a treatment course. Tumor-infiltrating lymphocytes (TIL) from melanoma patients were used to clone the genes encoding the tumor antigens responsible for clinical responsiveness. RESULTS: Thirty-three of 409 (8.1%) patients treated with high-dose bolus IL-2 achieved a complete response and 37 (9%) achieved a partial response. Complete regression was seen in 6.6% and 9.3% of patients with metastatic melanoma and renal cancer, respectively. Twenty-seven of these 33 completely responding patients (82%) remain in ongoing continuous complete response from 39 to more than 148 months from the onset of treatment. Tumor regressions were seen at virtually all organ sites. The absence of prior treatment with immunotherapy, the total dose of IL-2 administered, and the maximal rebound lymphocytosis after cessation of IL-2 correlated with achieving a complete response. Expression cloning techniques have identified a series of tumor antigens that are recognized by TIL grown from resected melanomas. These antigens are mainly melanoma/ melanocyte differentiation antigens, although mutated intracellular proteins can also serve as antigens. CONCLUSIONS: Treatment with high-dose bolus IL-2 mediates complete cancer regression in approximately 8% of patients with metastatic renal cancer and melanoma. The great majority of these patients will enter durable complete regressions and appear to be cured of their metastatic cancer. Thus, immunotherapy with high-dose bolus IL-2 should be considered as initial therapy for appropriately selected patients with metastatic melanoma and renal cell cancer. Identification of the tumor antigens mediating clinical response is opening new therapeutic possibilities for cancer treatment.

Adolescent↗

PubMed1997

Ultrastructure of rat lung following inhalation of ricin aerosol.

Ricin is one of a group of structurally related plant lectins and is extracted from the seeds of the Castor Oil plant, Ricinus communis. Groups of rats were exposed to ricin aerosol by inhalation, total LCt1-11.21 mg.min.m-3 (an approximate LCt30 exposure) and examined, using transmission electron microscopy, at intervals up to 48 h after exposure. The first signs of change in ultrastructure were seen at between 6 and 12 h post exposure in alveolar macrophages and took the form of apoptotic changes primarily in the nucleus. These included heterochromatin condensation at the nuclear periphery and crenulation of the nuclear membrane. There then followed a sequence of changes in the cells of the alveolar wall and blood/air barrier culminating in intra-alveolar oedema at 12 and 15 h after exposure. Damage was first observed in the capillary endothelium and type I epithelial cell changes were evident from 12 h post exposure onward. These changes appeared to be necrotic rather than apoptotic in nature and suggest that mechanisms other than a direct effect of ricin may be involved. Associated with these changes were mixed inflammatory cell infiltrates in the interstitium, isolated type II pneumocyte necrosis and evidence of microvascular microthrombosis. By 48 h after exposure, the intra-alveolar oedema appeared less marked with prominent hyperplasia of type II pneumocytes. The identification that apoptosis of alveolar macrophages plays a significant part in the mechanism of toxicity following exposure to ricin raises the possibility of developing new therapeutic strategies against poisoning by ricin.

Aerosols↗

PubMed1996

Combination therapy with interferon-gamma and interleukin-2 for the treatment of metastatic melanoma.

The toxicity and clinical response to treatment with the combination of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) in patients with metastatic melanoma was evaluated. From May 1993 through February 1994, 20 patients were treated with 24 courses of IFN-gamma with or without IL-2. A 7-day course of subcutaneous IFN-gamma alone was administered to cohorts of two or three patients each at doses of 0.1, 0.2, or 0.3 mg/m2. Thirteen patients received escalating doses of IFN-gamma between 0.2 and 0.5 mg/m2 followed by the intravenous (i.v.) administration of IL-2 (720,000 IU/kg) given three times a day. A treatment course consisted of two cycles (maximum of 15 doses of IL-2 per cycle) separated by a 10-day interval. Five additional patients were treated with five courses of IFN-gamma, IL-2, and tumor-infiltrating lymphocytes (TILs). All patients treated had the diagnosis of metastatic melanoma. The maximal tolerated dose of subcutaneous IFN-gamma was established at 0.3 mg/m2 with dose-limiting hepatotoxicity. Immunohistochemistry analyses showed detectable upregulation of MHC class I alleles in one (8%) of 12 patients. Two of 20 patients who received the combination of IFN-gamma and IL-2 had responses, one partial and one complete response. The duration of response was 7 months for the partial response and 12 months for the complete response. IFN-gamma was tolerated with minimal side effects of nausea, vomiting, malaise, and decreased hematopoiesis. No increased toxicities were found with the combination treatment, as compared with IL-2 alone. One death occurred on the third day of treatment with IFN-gamma alone from hemorrhage into brain metastases. There were no responders in the five patients who received the combination treatment of TIL, IL-2, and IFN-gamma. From these findings, we conclude that further studies looking at this combination treatment are not warranted.

Adult↗

PubMed1996

Vitiligo in patients with melanoma: normal tissue antigens can be targets for cancer immunotherapy.

Patients with metastatic renal cell cancer and metastatic melanoma treated with high-dose interleukin-2-based immunotherapy were prospectively evaluated for the development of vitiligo. All patients seen in the Surgery Branch, NCI Immunotherapy Clinic, who had been followed for at least 1 year were evaluated. Of 104 patients with metastatic renal cancer none developed vitiligo, though vitiligo was seen in 11 of 74 (15%) patients with metastatic melanoma (p2 = 0.0001). No vitiligo was seen in 27 patients who did not respond to immunotherapy, although vitiligo was seen in 11 of 43 (26%) melanoma patients who had an objective response to IL-2-based immunotherapy (p2 = 0.0002). These findings provide further evidence that the presence of a growing melanoma can sensitize patients to melanocyte-differentiation antigens and that the immune response against these antigens is associated with cancer regression in patients undergoing immunotherapy.

Antigens, Neoplasm↗

PubMed1995

The use of polyethylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2.

BACKGROUND: Conjugation of polyethylene glycol to recombinant human interleukin-2 (IL-2) results in a compound, polyethylene glycol-modified IL-2 (PEG-IL-2) that retains the in vitro and in vivo activity of IL-2, but exhibits a markedly prolonged circulating half-life. In mice, one dose of PEG-IL-2 results in tumor regression comparable to that achieved with multiple bolus doses of IL-2. Based on these preclinical studies, a Phase I study with PEG-IL-2 was undertaken in patients with metastatic renal cell carcinoma (RCC) and melanoma. Then, to exploit the higher peak levels attained with IL-2 and the improved trough levels of PEG-IL-2, a combination regimen beginning with bolus IL-2 followed by low dose maintenance PEG-IL-2 was devised and tested for efficacy. METHODS: Patients with measurable metastatic melanoma or RCC were entered in a Phase I dose escalation trial of PEG-IL-2 given once a week by intravenous bolus. This trial then was repeated using a twice-a-week schedule. After determining the maximum tolerated dose (MTD) and a safe outpatient regimen for PEG-IL-2, a hybrid regimen combining an initial high dose IL-2 cycle followed by chronic maintenance with weekly PEG-IL-2 was devised. This regimen was compared with a standard regimen consisting of two cycles of high dose unconjugated IL-2 in a randomized prospective clinical trial. RESULTS: When given by intravenous bolus once a week, the MTD of PEG-IL-2 was 12 million IU/m2, with toxicities similar to those of unconjugated IL-2. A twice-a-week schedule was less well tolerated. Of 28 patients given 32 treatment courses at varied dose levels, there were two partial responses and one minor response. A total of 124 patients with metastatic melanoma or RCC were randomized to either standard unconjugated IL-2 therapy or the hybrid regimen. There was no treatment-related mortality in either arm, and the use of PEG-IL-2 resulted in a significant decrease in the need for intensive-care-unit care. The response rates (partial response and complete response) for patients with RCC and melanoma were 19% and 15%, respectively, for IL-2 alone and 17% and 11%, respectively, for the IL-2 and PEG-IL-2 combination. CONCLUSIONS: The combination of high dose IL-2 followed by PEG-IL-2 is a well tolerated regimen with significant activity against RCC and melanoma, but it shows no significant increase in antitumor activity compared with high dose IL-2 alone.

Adult↗

PubMed1995

The hematologic toxicity of interleukin-2 in patients with metastatic melanoma and renal cell carcinoma.

BACKGROUND: High dose interleukin-2 (IL-2) has been found to produce durable antitumor responses in some patients, benefiting most greatly those patients with melanoma and renal cell carcinoma. In this paper, the hematologic toxicity and changes resulting from high dose IL-2 alone administered by intravenous bolus are discussed. METHODS: One hundred ninety-nine consecutive patients treated with high dose IL-2 alone from January 1, 1988 to December 31, 1992 were included in this study. All patients had a diagnosis of metastatic melanoma or metastatic renal cell carcinoma and were treated at the National Cancer Institute (Bethesda, MD). RESULTS: Anemia, requiring erythrocyte transfusions, occurred in 14% of all treatment courses, with a median of two units of erythrocytes transfused. Severe leukopenia ( < 1,000 leukocytes/mm3) was rare (1.5% of all patients) and was not associated with any infectious complications. Severe thrombocytopenia ( < 30,000 platelets/mm3) occurred in 2.2% of all treatment cycles, with two patients experiencing a grade 3 hemorrhage, defined as gross blood loss, and one patient experiencing a grade 4 hemorrhage, defined as a debilitating blood loss. Defects in the coagulation pathway were common: abnormal partial thromboplastin time and prothrombin time values occurred in 64% and 25% of the treatment cycles, respectively. In addition, a mean clearance of 93% of lymphocytes from the peripheral blood was observed within 24 hours after initiating IL-2 therapy. This was followed by rebound lymphocytosis to a mean of 198% of baseline on posttreatment Day 4. There were no treatment-related deaths. CONCLUSIONS: During IL-2 therapy, adverse sequelae of anemia, thrombocytopenia, coagulopathy, and leukopenia were usually mild, transient and rarely limited therapy. A profound decrease in lymphocytes in the peripheral circulation occurred within 24 hours after initiating therapy, with a rebound occurring after stopping IL-2. No specific hematologic parameter was associated significantly with a patient's increased probability of responding to therapy.

Adolescent↗

PubMed1995

Posterior scleritis with annular ciliochoroidal detachment.

PURPOSE: We studied an unusual case of posterior scleritis in a patient with sarcoidosis. METHOD: The medical record was reviewed for clinical manifestation, course, and tests performed, including laboratory evaluations, fluorescein angiography, and ultrasonography. RESULTS: The patient had posterior scleritis and unilateral angle-closure glaucoma caused by an annular ciliochoroidal detachment. Sarcoidosis was confirmed by biopsy of an enlarged parotid gland. CONCLUSION: The mechanism of angle-closure glaucoma may not be clinically or echographically apparent for a week or more in patients who develop annular ciliochoroidal detachment. We also found an unusual association of sarcoidosis and annular ciliochoroidal detachment secondary to posterior scleritis.

Adrenergic beta-Antagonists↗

PubMed1995

Functional reach in wheelchair users: the effects of trunk and lower extremity stabilization.

Our purpose was to compare the effects of using wheelchair trunk and lower extremity stabilization on sitting trunk mobility and functional reach of wheelchair users. Seven subjects with paraplegia who averaged 35.6 years of age and nine able-bodied control subjects with an average age of 26.0 years participated in this study. Each subject's functional reach in the transverse and sagittal planes was video-recorded in each of three conditions, randomized in order: (1) without a belt; (2) with a neoprene chest belt; and (3) with a webbing thigh belt. The area circumscribed by each subject's functional reach under each condition was processed using the Motion Analysis Expert Vision Flextrak program. Functional reach in each belting condition was compared within each subject and between able-bodied controls and subjects with high and low thoracic levels of paraplegia. This study showed that in the sagittal plane, subjects with both high and low thoracic levels of paraplegia were able to substantially increase the area of their functional reach when using a chest belt when compared with the thigh belt or no-belt condition. The mean area of their sagittal plane functional reach increased by over 50% by stabilizing the chest to the wheelchair using a neoprene belt. However, in the transverse plane, only those individuals with lower thoracic paraplegia (T8 to L1) gained substantial benefit from chest strapping, increasing the area of their functional reach by a mean of 24%. In contrast, able-bodied control subjects gained no benefit in functional reach from either belting condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

HLA associations in the antitumor response against malignant melanoma.

In this study we analyzed the human leukocyte antigen (HLA) pattern of North American Caucasian patients with metastatic melanoma as compared with the North American Caucasian (NAC) population. We also investigated whether the HLA type of melanoma patients had an effect on their tolerance and response to interleukin-2 (IL-2)-based therapy. Four hundred twelve serologic phenotypes of Caucasian melanoma patients referred to the National Cancer Institute, National Institutes of Health, from February 1989 through December 1993 were collected by typing the patient's peripheral blood lymphocytes. Furthermore, 74 melanoma patients were typed for HLA class II by high-resolution sequence specific primer-polymerase chain reaction. Response rate and treatment-related toxicity in those patients receiving IL-2-based treatment (N = 272) were compared with HLA serologic types. The frequency of four HLA-B alleles was significantly different in the melanoma compared with the NAC population: of these, HLA-B5, -B8, and -B15 had a frequency falling between the NAC and the Northern European population. No other significant differences between melanoma patients and NAC population were noted for other HLA loci. A correlation was noted between HLA-DR3 and -DR4 alleles and decreased tolerance to IL-2, whereas homozygosity for HLA-DR decreased the chance of response. There were no significant associations between HLA type and response. It is unlikely that the associations noted between some HLA-B alleles and melanoma bear significantly on the etiology of the disease. The differences seen between American melanoma patients and the NAC population are probably best explained by geographical ancestry. The association between HLA-DR and tolerance to IL-2 therapy noted in this study may offer insight toward the understanding of mechanisms regulating the cascade of events after the systemic administration of IL-2.

Gene Frequency↗

PubMed1995

Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone.

The purpose of this prospective study was to determine the incidence of thyroid dysfunction in cancer patients receiving immunotherapy with interleukin-2 (IL-2) alone, and to assess the relationship of hypothyroidism to clinical response. A cohort of 281 consecutive patients with metastatic melanoma or renal carcinoma were treated with IL-2 alone from July 1, 1989 until June 30, 1993. The majority (n = 216) received high-dose IL-2 and the remainder (n = 65) received low-dose therapy. Thyroid function was measured before, during, and after immunotherapy. Forty-one percent of initially euthyroid patients developed thyroid dysfunction after starting high-dose IL-2-alone therapy. The most common abnormality was hypothyroidism, occurring in 35% of patients, although moderate or severe hypothyroidism requiring thyroid hormone replacement occurred in 9% of patients. Hypothyroidism was related to duration of IL-2 therapy and was not associated with clinical response. Hyperthyroidism developed in 7% of previously euthyroid patients receiving high-dose IL-2. Overall, the incidence of thyroid dysfunction was similar in the high- and low-dose IL-2 regimens. In conclusion, thyroid dysfunction is a common sequela of IL-2 therapy. Thyroid function should be measured routinely in cancer patients receiving IL-2-based treatment. It is recommended that thyroid hormone replacement be given to patients with moderate or severe hypothyroidism.

Adolescent↗

PubMed1995

Combination therapy with interferon alfa-2a and interleukin-2 for the treatment of metastatic cancer.

PURPOSE: Here we report the long-term follow-up evaluation of a phase I/II study of toxicity and response of combination interferon alfa-2a (IFN alpha) and interleukin-2 (IL-2) in patients with metastatic cancer. PATIENTS AND METHODS: From November 1987 through October 1990, 189 patients were treated with 379 courses. IFN alpha (3 x 10(6) U/m2) was administered three times per day as an intravenous (IV) bolus with IV IL-2 2.6 x 10(6) IU/m2 (six patients, group 1), 7.8 x 10(6) IU/m2 (32 patients, group 2), or 11.7 x 10(6) IU/m2 (26 patients, group 3). Subsequently, IFN alpha dose was escalated to 6 x 10(6) U/m2 plus IL-2 11.7 x 10(6) IU/m2 (22 patients, group 4). Two further dosage schedules of IL-2 were tested at 7.8 x 10(6) IU/m2 (29 patients, group 5) and 15.6 x 10(6) IU/m2 (74 patients, group 6); however, because of IFN alpha-related toxicity, these two groups received IFN alpha once per day (6 x 10(6) U/m2). A treatment course consisted of two cycles (maximum, 15 doses per cycle) separated by a 10-day interval. RESULTS: All patients were assessable for response: 82 patients had melanoma, 75 renal cell carcinoma (RCC), and 16 colorectal cancer. There were two treatment-related deaths. The objective response rate was 23% (43 patients). Response rates were 17%, 19%, 19%, 32%, 41%, and 16%, respectively, for groups 1 through 6. Ten responses are still ongoing (nine in RCC patients) at 57 to 74 months, and 21 patients are alive, for an overall 5-year survival rate of 11%. The median potential follow-up period was 65 months. Although a significantly higher response rate was noted for group 4 (highest dose of IFN alpha three times per day), no benefit for survival and increased toxicity were noted in this group. CONCLUSION: Based on these findings, we conclude that further studies of this combination treatment are not warranted.

Adolescent↗