Cristina de Leon

Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma

This study was performed to obtain safety and survival data for patients with histologically confirmed recurrent glioblastoma multiforme (GBM) who received intralesional lymphokine-activated killer (LAK) cells following surgery. LAK cells were generated by incubating peripheral blood mononuclear cells with interleukin-2 for 3 to 5 days in vitro. Forty patients with pathologic confirmation of GBM at surgery had placement of autologous LAK cells into the tumor cavity. The 23 men and 17 women had a median age of 48 years (range 21–76). The median interval from the original diagnosis of glioma to LAK treatment was 10.9 months. Patients received an average of 2.0 ± 1.0 × 109 LAK cells, with viability of 91 ± 6.8%. Treatment was well tolerated; there was one death within 60 days. At a median follow-up of 2.3 years, median survival post-LAK was 9.0 months; 1-year survival was 34%. Gender, age, location of tumor, LAK cell lytic activity, number of cells implanted, and inclusion of interleukin-2 at cell instillation were not correlated with outcome. Median survival from the date of original diagnosis for 31 patients who had GBM at initial diagnosis was 17.5 months versus 13.6 months for a control group of 41 contemporary GBM patients (p2 = 0.012). This treatment is safe and feasible. The median survival rates are higher than reported in most published series of patients who underwent reoperation for recurrent GBM. A randomized trial would be needed to establish therapeutic benefit.

Phase II trial of dendritic cells loaded with antigens from self-renewing, proliferating autologous tumor cells as patient-specific antitumor vaccines in patients with metastatic melanoma: final report.

UNLABELLED Between 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 microg 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).

Irradiated Cells from Autologous Tumor Cell Lines as Patient-Specific Vaccine Therapy in 125 Patients with Metastatic Cancer: Induction of Delayed-Type Hypersensitivity to Autologous Tumor is Associated with Improved Survival

OBJECTIVE We established short-term cultures of pure tumor cells for use as autologous tumor cell vaccines in an effort to study the effects of patients-specific immunotherapy. PATIENTS AND METHODS Surgically resected fresh tumor was obtained from patients with metastatic cancer. Successful tumor cell lines (5 x 10(7)) were expanded to 10(8) cells, irradiated, and cryopreserved for clinical use. Following a baseline test of delayed-type hypersensitivity (DTH) to an i.d. injection of 10(6) irradiated autologous tumor cells, patients received 3 weekly s.c. injections of 10(7) cells, had a repeat DTH test at week-4, then received monthly vaccinations for 5 months. A positive DTH test was defined as > or = 10 mm induration; survival was determined from the first DTH test. RESULTS Short-term cell lines were successfully established for 299/695 patients (43%). Vaccines were prepared for 231 patients, 142 of whom were treated, and 125 had a baseline DTH test recorded. Median follow up at the time of analysis was greater than 5 years. There was no difference in survival for any of the following: gender, age > 50 years, melanoma histology, anergy to common recall antigens or baseline DTH test result. Only 17 patients had a positive DTH at baseline (14%), but DTH converted from negative to positive in 31/80 (39%) of those who were tested, and in 31/108 (29%) of all patients (intent-to-convert analysis). For the 48 patients who were DTH-positive at entry, or converted to DTH-positive, the median survival was 30.5 months and 5-year survival 41% compared to 11.4 months and 9% 5-year survival for 77 patients whose DTH was never positive (P2 = 0.003). However, survival was even better for patients whose DTH test converted to positive compared to patients who were DTH-positive at baseline (median 37.5 vs 11.9 mos, P2 = 0.066). CONCLUSION This patient-specific, cell culture-derived, autologous tumor cell vaccine induced anti-tumor immune reactivity that was associated with improved survival in patients with advanced cancer.

Treatment of Kidney Cancer with Autologous Tumor Cell Vaccines of Short-Term Cell Lines Derived from Renal Cell Carcinoma

BACKGROUND We established short-term cultures of autologous tumors from patients with renal carcinoma for use as active specific immunotherapy (i.e., autologous vaccine). METHODS Between 9/91 and 9/99 the cell biology laboratory of the Hoag Cancer Center received 69 kidney tumor samples that had been surgically excised, including 43 primary tumors and 26 metastatic lesions. Efforts were made to establish short-term tumor cell cultures to use as autologous tumor cell vaccines. Prior to treatment, patients underwent a baseline skin test for delayed tumor hypersensitivity (DTH) and then received s.c. injections of 10 million irradiated tumor cells that were given with various adjuvants weekly x3 and then monthly x5. RESULTS Cell lines were established for 55/69 patients (80%) including 36/43 (84%) from primary tumors and 19/26 (73%) from distant metastases. Vaccines were prepared for 41 patients; 27 were treated. At the time of this analysis, follow up data was available for 26 patients with a median follow up > 5 years. Treatment was well-tolerated. Of 10 patients who had no evident disease at the time of treatment, nine were alive 1-8 years later; 5/8 had conversion of their DTH test from negative to positive. For 16 patients with measurable metastatic disease at the time of treatment, there were no objective tumor responses; their median survival was 5.0 months. Among these 16 patients, only 1/8 DTH tests converted, but three had a positive baseline DTH test; one was previously treated with interleukin-2 and tumor infiltrating lymphocytes and two others were previously treated with autolymphocyte therapy. CONCLUSIONS Vaccine therapy with short-term cultures of autologous tumor cells is feasible, well-tolerated and associated with conversion of DTH and long-term survival in patients who are free of disease at the time treatment is initiated. However, significant anti-tumor responses were not seen in patients with measurable disease at the time vaccine treatment was initiated.

Dendritic Versus Tumor Cell Presentation of Autologous Tumor Antigens for Active Specific Immunotherapy in Metastatic Melanoma: Impact on Long-Term Survival by Extent of Disease at the Time of Treatment.

Abstract In patients with metastatic melanoma, sequential single-arm and randomized phase II trials with a therapeutic vaccine consisting of autologous dendritic cells (DCs) loaded with antigens from self-renewing, proliferating, irradiated autologous tumor cells (DC-TC) showed superior survival compared with similar patients immunized with irradiated tumor cells (TC). We wished to determine whether this difference was evident in cohorts who at the time of treatment had (1) no evidence of disease (NED) or (2) had detectable disease. Eligibility criteria and treatment schedules were the same for all three trials. Pooled data confirmed that overall survival (OS) was longer in 72 patients treated with DC-TC compared with 71 patients treated with TC (median OS 60 versus 22 months; 5-year OS 51% versus 32%, p=0.004). Treatment with DC-TC was associated with longer OS in both cohorts. Among 70 patients who were NED at the time that treatment was started, OS was better for DC-TC: 5-year OS 73% versus 43% (p=0.015). Among 73 patients who had detectable metastases, OS was better for DC-TC: median 38.8 months versus 14.7 months, 5-year OS 33% versus 20% (p=0.025). This approach is promising as an adjunct to other therapies in patients who have had metastatic melanoma.

Radioimmunotherapy for Non-Hodgkin's Lymphoma With Yttrium 90 Ibritumomab Tiuxetan

The increasing incidence of non-Hodgkins lymphoma (NHL), coupled with the lack of optimal treatment options, has prompted the development of novel treatments. Of these, radioimmunotherapy is one of the most promising. Two of the radiolabeled monoclonal antibody therapies being studied in the treatment of NHL are yttrium 90 (90Y) ibritumomab tiuxetan and iodine 131 (131I) tositumomab. The radionuclides 90Y and 131I emit beta radiation; 131I also emits gamma radiation, thus requiring more elaborate precautionary measures to limit radiation exposure. The monoclonal antibody portions of the drugs target the CD20 surface antigen that is present on the majority of B-cell lymphomas, resulting in direct radiation to the targeted cells, as well as indirect targeting of adjacent cells (known as the crossfire effect). Clinical trials of 90Y ibritumomab tiuxetan in patients with NHL have produced promising results. The safe and effective use of radioimmunotherapy requires a multidisciplinary team approach in which nurses play a central role.

Treatment of Human Solid Malignancies with Autologous Activated Lymphocytes and Cimetidine: A Phase II Trial of the Cancer Biotherapy Research Group

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 x 10(9) 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)-alpha, interleukin (IL)-1beta, interferon-gamma, and IL6, but no IL-2. Subsequently patients underwent up to 6 monthly leukaphereses to collect 2-5 x 10(9) 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 x 10(9)) 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.

Short-Term Tumor Cell Lines from Breast Cancer for Use as Autologous Tumor Cell Vaccines in the Treatment of Breast Cancer

OBJECTIVE We tried to establish short-term cultures of autologous tumors from patients with breast carcinoma for potential use as active specific immunotherapy (i.e., autologous vaccine) after resection of primary breast cancer, and/or for the treatment of metastases. METHODS Between 10/90 and 12/99 the cell biology laboratory of the Hoag Cancer Center attempted to establish short-term tumor cell lines from 115 breast cancer specimens from 56 primary breast lesions, 17 axillary nodes, 14 other lymph node/soft tissue sites, 10 chest wall recurrences, and 6 thoracentesis of malignant pleural effusions. Success was defined by growth of 5 x 10(7) viable cells whose malignant nature and breast cancer origin was confirmed by histology of the submitted tissue, cell morphology and antigenic phenotyping. Variables associated with successful growth of short-term cell lines were examined. RESULTS Expansion to 5 x 10(7) cells was achieved for only 8/115 samples [7%] including two from chest wall recurrences, and one each from a supraclavicular node, an umbilical node, liver, omentum, and pleural fluid. Two of the successful cell lines were established from tissue that originally had been cryopreserved; the others were initiated from fresh tumor. The success rate was better from regional/distant metastases 7/55 (13%) compared to primary tumors 1/56 (1.8%) (p = 0.063). The success rate for tumors harvested at Hoag Hospital was 4/97 (4%) compared to 4/14 from (31%) distant sites, but all but one of the tumors from a distant geographic site was a metastatic lesion. Tumor cell lines were successfully established from metastatic lesions ranging in size from < 1.0 g to 19 g. Four patients were treated with their autologous vaccine in the setting of chemotherapy-refractory metastatic disease without any significant toxicity. CONCLUSIONS We were unable to establish short-term cell lines for most patients with primary or metastatic breast cancer using this methodology. However, two long-term cell lines have been established and characterized. Treatment with the autologous irradiated cell product was not associated with acute toxicity.

Acute and Chronic Complications in Patients with Ductal Carcinoma in Situ Treated with Intraoperative Radiation Therapy

Intraoperative radiation therapy (IORT) delivers radiation therapy directly to the tumor bed at the time of surgery. Minimal data are available regarding IORT complications in patients diagnosed with ductal carcinoma in situ (DCIS) using the Xoft® Axxent eBx® System. 146 patients with pure DCIS received X‐ray based IORT therapy using the Xoft® Axxent eBx® System at Hoag Memorial Hospital Presbyterian between June 2010 to April 2016 and were accrued to an IORT data registry study. The protocols were approved by the institutional review board and met the guidelines of their responsible governmental agency. Data were collected at 1 week, 1 month, 6 months, 1 year, and thereafter yearly. Acute complications were defined as those occurring within the first month. Chronic complications were those that persisted beyond 6 months. Acute complications were observed in 18% of patients and included hematomas that required drainage, an infection treated with antibiotics, and erythema. Chronic complications were observed in 12% of patients and included a seroma, fibrosis and hyperpigmentation. The majority of acute and chronic problems were mild (Grade I). If Grade I erythema, fibrosis, and hyperpigmentation are not included, only 11/146 patients (7.5%) had significant complications. The rate of acute and chronic complications from X‐ray IORT in DCIS patients was low compared to historical toxicity rates observed in DCIS patients treated with whole breast irradiation. Our data indicate that X‐ray IORT can be utilized safely in patients diagnosed with DCIS.

Mesotelioma maligno pleural. Características clínicas, factores pronósticos y tratamiento

El mesotelioma maligno pleural es una enfermedad letal a corto plazo con independencia del tipo de tratamiento realizado. Se han analizado de forma retrospectiva las caracteristicas clinicas, los factores pronosticos y los tratamientos realizados en 41 pacientes seguidos en los ultimos 13 anos en un servicio de oncologia. El 32% de los pacientes tenia una exposicion previa al asbesto, el 61% ≤ 60 anos, el 71% un indice de Karnofsky ≥ 80% y el 63% un estadio I de Butchart. El primer sintoma al diagnostico fue el dolor en el 66% de los casos y la mediana de tiempo desde el primer sintoma al primer diagnostico fue de 3 meses. Treinta pacientes nunca obtuvieron una remision completa (RC) de su enfermedad: 15 tratados con quimioterapia (QMT) paliativa, uno radioterapia (RT) paliativa, 5 con pleurectomia parcial (PP) mas RT y/o QMT y 9 con tratamiento sintomatico de soporte. Solo 11 (27%) pacientes obtuvieron una remision completa de su enfermedad al Analizar el tratamiento: 7 pacientes tratados con neumonectomia extrapleural, 2 ciclos de QMT y RT y 4 pacientes tratados con PP con o sin RT y/o QMT posterior. Solo tres de estos pacientes estan vivos sin recidiva a mas de un ano de seguimiento. La mediana de supervivencia de los 41 pacientes fue de 8 meses. En el analisis univariado, los factores pronosticos que influenciaron la supervivencia fueron la edad y el indice de Karnofsky. El grupo seleccionado de pacientes tratados inicialmente con cirugia obtuvo una supervivencia superior. En conclusion, solo el indice de Karnofsky y la edad fueron factores pronosticos en nuestra serie. La mejor supervivencia de los pacientes tratados inicialmente con cirugia estaria en relacion con la seleccion previa de estos.