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AbstractInterleukin-2 (IL-2) was the preferred treatment for medically fit patients with advanced kidney cancer, but recently, several targeted therapies have been approved for metastatic renal cell carcinoma. We wished to determine the long-term survival rate for patients with kidney cancer treated with IL-2 and whether the use of intense inpatient IL-2 has declined since the introduction of targeted therapies. Patients who received IL-2 were identified from clinical trial enrollment, pharmacy logs, and financial billing records. Survival was determined from the earliest date of IL-2 therapy. There were 79 patients hospitalized for high-dose infusional IL-2 between March 1989 and March 2009. Median age was 58 years, and 27% were older than 65 years at the time of treatment. At the time of this analysis, 72 patients had deceased. Median survival was 9.9 months, but 5-year survival was 19.4%. The average number of patients with IL-2 increased from 2.2 per year during 1989–1992 to 5.6 during 1993–2001 after FDA approval, but dropped to 2.0 during 2002–2009. High-dose IL-2 is associated with a 5-year survival rate that is higher than objective response rates, suggesting a delayed immunotherapy benefit for some patients. The use of intensive IL-2 has declined dramatically in recent years, but unless a long-term survival benefit can be shown for these new targeted products, we feel that inpatient IL-2 remains the preferred initial treatment. [ABSTRACT FROM AUTHOR]

AbstractA patient with metastatic melanoma who experienced a durable complete response after treatment with a patient-specific vaccine has been described in this article. This 59-year-old woman presented with cervical spine metastases and, within the year, had experienced local disease progression and, despite various therapies, metastases to the axilla, rectum, gall bladder, and multiple soft-tissue sites. She had previously received radiation therapy, combination chemotherapy, interleukin-2 plus interferon biotherapy, and gamma knife radiosurgery, and undergone multiple surgical resections. At the time vaccine therapy was initiated, she had multiple, new, measurable, soft-tissue metastases that were increasing in size. She was treated with a vaccine consisting of autologous dendritic cells incubated with irradiated tumor cells from an autologous tumor cell line and suspended in granulocyte-macrophage colony stimulating factor (GM-CSF), with subcutaneous injections once a week for 3 weeks and monthly for 5 months. There was evidence of disease regression by the completion of therapy. A few months later a complete response was documented by radiologic scans, and subsequently reconfirmed at 6-month intervals. She remains in complete remission >2.5 years after starting the vaccine, and >2 years after completing the vaccine, and survives >4 years after her initial presentation with bone, bowel, and lymph node metastases. This is the first time she has been in a complete remission since her initial diagnosis. Patient-specific vaccines can sometimes induce durable complete regression of progressing soft-tissue melanoma metastases. [ABSTRACT FROM AUTHOR]

AbstractBetween January 2001 and September 2007, we treated 54 metastatic melanoma patients with patient-specific tumor cell vaccines consisting of dendritic cells (DCS), derived from their peripheral blood cells that were cultured in interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor (GM-CSF), which had phagocytosed irradiated autologous tumor cells from a continuously proliferating, self-renewing, autologus tumor cell (TC) culture. The loaded DCs were injected subcutaneously in 500 μg of GM-CSF weekly x three, and then monthly for 5 months, for a total of up to 8 injections. The 34 men and 20 women had a median age of 50.5 years; 32 had M1c (visceral metastases and/or elevated lactate dehydrogenase) as their most advanced disease stage. Overall, 83% had received other systemic therapies, including interferon-alpha (n= 20), biochemotherapy (n= 19), GM-CSF (n= 19), chemotherapy (n= 16), IL-2 (n= 13), and other investigational vaccines (n= 7). Patients received an average of 7.4 vaccinations. Treatment was well-tolerated, with most patients experiencing only mild local pruritus and/or erythema. A positive delayed-type hypersensitivity reaction to purified autologous tumor cells was observed at baseline in only 1 of 54 patients, compared to 12 of 54 following vaccination (p= 0.001). The projected 5-year survival rate is an impressive 54% at a median follow-up of 4.5 years (range, 2.4–7.4) for the 30 surviving patients. This survival was superior to that observed following vaccination with irradiated TC in 48 melanoma patients in a previous trial (64 versus 31 months, p= 0.016). This patient-specific vaccine warrants further investigation, based on its safety and encouraging survival rates. (Clinical Trial Number: NCI-V01-1646). [ABSTRACT FROM AUTHOR]

Seventy-four (74) patients with metastatic melanoma were treated with patient-specific vaccines derived from autologous tumor cell lines. Cryopreserved irradiated tumor cells were injected weekly for 3 weeks, then monthly for 5 months. At a median follow up >6 years, the median event-free survival (EFS) was 4.5 months, with 13 patients alive and progression free 6–12 years later. Median overall survival (OS) was 20.5 months, with 29 5-year OS. Tumor response rate was 9 among the 35 patients with evaluable disease who received at least 3 injections. Better survival was observed for patients who had minimal rather than clinically evident metastatic disease at the time vaccine therapy was initiated (5-yr OS 47 vs. 13;p 12 million cells per injection (5-yr EFS OS 35 vs. 24;p 0.041 andp 0.034). There was a trend toward better EFS for those who had a positive delayed type hypersensitivity (DTH) reaction to an intradermal injection of 1 million irradiated tumor cells at baseline, or converted to positive after 3 injections, compared to those whose DTH remained negative (5-yr EFS 39 vs. 18;p 0.159). This treatment approach is feasible, produces minimal toxicity, and is associated with longterm survival in a significant proportion of patients. [ABSTRACT FROM AUTHOR]

We conducted a multicenter, community-based phase II trial of PCR biochemotherapy (pentostatin 4 mgm2, cyclophosphamide 600 mgm2, and rituximab 375 mgm2) every 3 weeks for up to 6 cycles in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The study was stopped after enrolling 24 patients because of diminished investigator interest after 8 patients discontinued treatment because of adverse events, and 5 others died during treatment. The median age of patients was 69 years; 11 patients were over age 70, and 71 had Rai stage III or IV disease. The response rate among the 17 evaluable patients who completed 3 cycles of therapy was 58 (35–81, 95 confidence interval), with 2 complete responders (both greater than 70 years of age) and 7 partial responders. No patients developed progressive disease while receiving PCR. This is the first report of a trial in CLL utilizing a combination of purine analog, alkylator, and rituximab, in which most patients were older than 65 years and had high-risk disease. PCR is active in CLLSLL, but appears to be less active and associated with more complications in the community setting, compared to trials with younger, lower risk patients who travel to academic referral centers for treatment. [ABSTRACT FROM AUTHOR]

Objective: We conducted a phase II trial in metastatic renal cell cancer of outpatient subcutaneous (s.c.)interferon-α2b (IFN), followed by an inpatient hybrid schedule of bolus and continuous interleukin-2 (IL-2). Methods: Treatment consisted of monthly IFN 10 MU/m2 s.c. for 4 consecutive days, followed by 36MIU/m2 bolus IL-2, then 72-hour continuous intravenous (i.v.) infusion of 18 MIU/m2 IL-2 per day. BetweenMay 1997 and June 2000, 25 men and 11 women enrolled, with a median age of 57 years (range,42–77), including 9 patients over 65. Prior treatment included nephrectomy (31), radiation (8), biotherapy(7), and chemotherapy (4). Sites of disease included 26 lung, 13 lymph node, 9 bone, 8 liver, 4 kidney,and 4 adrenal locations. Patients received an average of 3.1 treatment cycles (range, 1–6). Results:There was 1 complete and 3 partial responses, for a response rate of 11% (3% to 27%; 95% confidenceinterval [CI]); 40% had stable disease. Median failure-free survival was 2.5 months; median overall survivalwas 15.0 months. The 1-, 2-, and 5-year survival rates were 53%, 30%, and 12%, respectively. Only8 patients required a reduction in IL-2 dose. The most frequent grade 3 or 4 toxicities were 11% fatigue,9% renal insufficiency, and 7% hypotension. Conclusions: Response and survival rates were similar tothose seen in other multicenter trials using inpatient high-dose IL-2. [ABSTRACT FROM AUTHOR]

Short-term autologous tumor vaccines were established and used to treat metastatic melanoma patients. Serum samples obtained prior to (week 0) and after three vaccinations (week 4) were assayed for interleukin (IL)-2, interferon (IFN)-γ, IL-4, and IL-10. Results (mean ± SD) for 30 patients who had matching serum samples obtained at weeks 0 and 4 were: week 0, IL-2, 122 ± 320 pg/mL; IFN-γ, 0.1 ± 0.4 IU/mL; IL-4, 10.0 ± 19 pg/mL; IL-10, 159 ± 237 pg/mL; week 4: 119 ± 308 for IL-2; 0.1 ± 0.4 for IFN-γ; 16 ± 29 for IL-4, and 210 ± 273 for IL-10. Medium conditioned by tumor cell lines demonstrated relatively low levels of secreted IL-10 (3.5 ± 4.2 pg/106 cells/mL/96 hours), which would not account for the observed serum levels. In conclusion, the serum cytokine pattern from these patients suggests that the immune system is being modulated prior to and subsequent to vaccination. [ABSTRACT FROM AUTHOR]

Objective: The Cancer Biotherapy Research Group conducted a clinical trial to verify encouraging reports of antitumor activity of autolymphocyte therapy. Patients and Methods: Patients with a variety of advanced solid malignancies underwent an initial leukapheresis procedure to collect about 5 × 109 autologous lymphocytes that were stimulated in vitro for 3 days with anti-CD3 monoclonal antibody in the presence of indomethicin and cis-retinoic acid to obtain media that was frozen in aliquots. This media contained significant amounts of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon-γ, and IL6, but no IL-2. Subsequently patients underwent up to 6 monthly leukaphereses to collect 2-5 × 109 autologous lymphocytes that were incubated in vitro for 6 days in the cryopreserved media containing autologous lymphokines, resulting in a cell population enriched for noncytotoxic T-helper lymphocytes. These were administered intravenously monthly for up to 6 months with daily oral cimetidine at a dose of 600 mg po qid, which was given throughout the treatment period. Tumor response was assessed every 2 months. Results: There were 47 patients (25 women and 22 men) with a median age of 55 years (range 31-79). One hundred seventy four treatments were delivered and were well tolerated. A mean of 2.05 ± 1.46 (range 0.82-12.8 × 109) cells were infused. Eighty-five percent received two or more doses; 19% received six doses. Objective tumor responses were observed in 1/15 renal cell, 1/13 colorectal, 0/6 breast, 0/5 lung, 0/2 gastric, 0/2 sarcoma, 0/1 pancreas, 0/1 prostate, 0/1 melanoma, and 0/1 eccrine. Forty-three patients have died. Median survival was 8.8 months, 1-year survival 35%, and 2-year survival 15%. Conclusion: This complex treatment program was feasible. Infusion of these cells was well tolerated. Some antitumor activity was seen in patients with renal cell cancer and colorectal cancer. [ABSTRACT FROM AUTHOR]