Kidney Cancer - metastasis vaccine

Treatment of kidney cancer with autologous tumor cell vaccines of short-term cell lines derived from renal cell carcinoma.

Dillman RO, Barth NM, VanderMolen LA, Garfield DH, De Leon C, O'Connor AA, Mahdavi K, Nayak SK.

Hoag Cancer Center, One Hoag Drive, Building 41, Newport Beach, California 92658, USA. rdillman@hoaghospital.org

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.

PMID: 11279797 [PubMed - indexed for MEDLINE]




Cancer Biother Radiopharm. 2002 Feb;17(1):51-66.


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.

Dillman RO, Beutel LD, Barth NM, de Leon C, O'Connor AA, DePriest C, Nayak SK.

Hoag Cancer Center, One Hoag Drive, Building 41, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

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.

PMID: 11915174 [PubMed - indexed for MEDLINE]






Crit Rev Oncol Hematol. 2001 Jul-Aug;39(1-2):115-23.



Short-term autologous tumor cell lines for the active specific immunotherapy of patients with metastatic melanoma.

Dillman RO, DeLeon C, Beutel LD, Barth NM, Schwartzberg LS, Spitler LE, Garfield DH, O'Connor AA, Nayak SK.

Hoag Cancer Center, One Hoag Drive, Building 41, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

We established short-term cell lines for 108/170 (64%) patients with metastatic melanoma. Tumor cell numbers were expanded to 10(8), then cells were irradiated, aliquoted, and cryopreserved for clinical use. Vaccines have been used to treat 69 patients with clinical follow up for 33 who had measurable metastatic disease at the time vaccine therapy was initiated (METS), and 33 who had no evidence of disease (NED) at the time of vaccine therapy following surgical resection of metastases. The protocol called for a baseline test of delayed tumor hypersensitivity (DTH), three weekly injections, a repeat of the DTH test, then monthly injections for an additional 5 months.

Objective tumor responses were noted in 3/26 (12%) patients who received a minimum of three vaccinations, one complete, and two partial, with survivals of 36, 46+, and 78+ months. Only 6/64 (9.4%) had a positive DTH (>10 mm) at baseline, including three METS, all of whom progressed within 4 months and died within a year, and three who are still NED after more than 5 years. Conversion of DTH from negative to positive was documented in 18/44 (41%) patients who were tested at week 0 and 4.

At a median follow up of greater than 5 years, the median overall survival (OS) was 40 months for "NED" with a 5-year survival rate of 39%, and 8.6 months with a 5-year survival rate of 10% for "METS" The 18 patients who had conversion of their DTH had a median event-free survival (EFS) of 15.8 months and 5-year EFS of 32% compared to 4.2 months and 9% for the 26 non-converters (P=0.012, two-tailed, log-rank test). Among patients who were NED when treatment started, the 12 patients whose DTH converted had a median overall survival of 61.4 months with 5-year survival of 63% compared to 9.7 months and 0% for the 13 non-converters (P=0.0026). This treatment approach is feasible, produces minimal toxicity, and is associated with long-term survival in a significant subset of patients.

PMID: 11418308 [PubMed - indexed for MEDLINE]




Cancer Biother Radiopharm. 2007 Jun;22(3):309-21.


Patient-specific vaccines derived from autologous tumor cell lines as active specific immunotherapy: results of exploratory phase I/II trials in patients with metastatic melanoma.

Dillman RO, DePriest C, DeLeon C, Barth NM, Schwartzberg LS, Beutel LD, Schiltz PM, Nayak SK.

Hoag Cancer Center, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

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 and p = 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.

PMID: 17651037 [PubMed - indexed for MEDLINE]








Cancer Biother Radiopharm. 1998 Jun;13(3):165-76.




Clinical experience with autologous tumor cell lines for patient-specific vaccine therapy in metastatic melanoma.

Dillman RO, Nayak SK, Barth NM, DeLeon C, Schwartzberg LS, Spitler LE, Church C, O'Connor AA, Beutel LD.

Hoag Cancer Center, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

Because of their patient specificity and proliferative capacity, tumor cell lines established from autologous metastatic melanoma tumor samples may be an excellent immunogen for patient-specific vaccine therapy. Between October 1990 and July 1996, the Hoag Cancer Center cell biology laboratory received 136 fresh metastatic melanoma samples from 122 different patients. Tumor cell lines were successfully established for 92 of 136 samples (68%), for 87 of 122 patients (71%). Successful cultures were expanded to 10(8) cells (total culture time about 8 weeks), confirmed to be sterile, irradiated, and stored frozen in aliquots of 10(7) cells. Vaccines were prepared from 72 lines, and 62 vaccines were used in 57 different patients. Subcutaneous vaccination took place on weeks 1, 2 and 3, and then monthly for a total of 6 months. A delayed tumor hypersensitivity skin test (DTH) was administered at week zero and week 4. Various adjuvants were co-administered including BCG, alpha- or gamma-interferon, and GM-CSF. Patients were monitored for failure-free survival (FFS) and overall survival (OS) from the date of the first vaccination. Follow-up data is available for 52 patients, 27 who had no evident disease (NED) at the time of vaccination and 25 who had metastatic disease at the time of treatment.

There were two partial responses which persisted 11.9 and 39.8+ months among the 25 patients who had detectable metastatic disease whün treatment was initiated (8%, 1 to 26%, 95%-Ci). Twenty patients had negative skin tests at week 0 and week 4; six were positive both times, and 13 converted their DTH from negative to positive, for a conversion rate of 13 of 33 (39%). Patients who received interferon-gamma and/or GM-CSF as an adjuvant had a higher rate of DTH conversion compared to patients who received other adjuvants (13 of 20 v 2 of 13, P = 0.003). For patients who were NED, nine of 19 (47%) converted their DTH test compared to four of 14 (29%) patients with metastatic disease (p = 0.33). For patients whose DTH converted from negative to positive after 3 weeks of vaccination, median FFS and OS were superior compared to patients whose DTH remained negative (19.4 v 4.0 months FFS, p = 0.0052 and 39.6 v 18.3 months OS, p = 0.0602).

The autologous cell line approach to active specific immunotherapy is feasible for patients who have resectable foci of metastatic disease. Administration of such patient-specific vaccines improves survival for those patients who are NED at the time of vaccination and convert their DTH skin test, compared to those whose DTH test remains negative.

PMID: 10850352 [PubMed - indexed for MEDLINE]




Cancer Biother Radiopharm. 2004 Oct;19(5):570-80.


Autologous tumor cell line-derived vaccine for patient-specific treatment of advanced renal cell carcinoma.

Dillman R, Barth N, Vandermolen L, Mahdavi K, Beutel L, de Leon C, DePriest C, Nayak S.

Hoag Cancer Center, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

AIM: We previously reported the laboratory methodology for producing patient-specific irradiated autologous tumor-cell products derived from short-term cultured tumor cells from resected renal cell carcinoma, and described preliminary clinical results. In this study, we report the final clinical results and efforts to define vaccine potency on the basis of clinical outcome for these 25 patients with advanced renal cell carcinoma. MATERIALS AND METHODS: Approximately 10(8) cells from successful short-term cell lines were irradiated, frozen in aliquots of 10(7) cells, then thawed and administered subcutaneously (s.c.) once a week for 3 weeks, then once a month for 5 months. Patients included 19 men and 6 women, who were 43-82 years of age. Six (6) patients had a large primary lesion, 2 patients had regionally advanced disease, 3 patients had been rendered disease-free by surgical resection of distant metastases, and 14 patients had measurable distant metastatic disease. RESULTS: The vaccines were well tolerated, and no delayed autoimmune effects were documented. Delayed-type hypersensitivity (DTH) tests of irradiated tumor cells were positive in only 1 of 25 patients at week 0, but converted to positive in 6 of 18 patients of DTH-negative patients who were retested at week 4. Objective response rate in patients who had measurable metastatic disease was 0 of 14 patients. With a median follow-up of greater than 7 years from the date of the first DTH test, median survival is 33.4 months, 5-year survival is 43%, and 10 patients are alive 3-12 years later. The 7 DTH+ patients survived a median of 2.5 years, and 3 patients are alive after 3, 4, and 7 years. There was no correlation between the number of irradiated cells or viable irradiated cells injected and tumor DTH reactivity or survival. CONCLUSION: This approach is feasible and the therapy is well tolerated, but clinical benefit was not established in this trial. Any further exploration of this product should be limited to the adjuvant setting in a randomized trial.

PMID: 15650449 [PubMed - indexed for MEDLINE]




Cancer Biother Radiopharm. 2004 Oct;19(5):658-65.


Phase I/II trial of melanoma patient-specific vaccine of proliferating autologous tumor cells, dendritic cells, and GM-CSF: planned interim analysis.

Dillman R, Selvan S, Schiltz P, Peterson C, Allen K, Depriest C, McClay E, Barth N, Sheehy P, de Leon C, Beutel L.

Hoag Cancer Center, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

AIM: The aim of this study was to investigate the feasibility, safety, and clinical efficacy of patient-specific dendritic cell vaccines in patients with metastatic melanoma. A planned interim analysis was conducted on the first 20 patients.

METHODS: Tumor cell lines were established from metastatic tumor, expanded to 200 million cells, and then incubated with interferon-gamma for patients who were candidates for therapy. Cells were irradiated and cryopreserved. Patients underwent leukapheresis to obtain mononuclear cells that were cultured in the presence of IL-4 and GM-CSF to produce dendritic cells, which were incubated with cryopreserved, irradiated tumor cells, and then stored in aliquots of about 20 million cells for subcutaneous (s.c.) injections with GM-CSF once a week for 3 weeks, then once a month for 5 months.

RESULTS: The first 20 eligible patients included 10 men and 10 women, with a median age of 48 years (range, 16-79 years). Three (3) patients had brain metastases, and 13 patients had experienced disease progression after biochemotherapy. At the time of vaccine treatment, 6 patients had evaluable metastatic disease, while 14 patients lacked measurable disease. Vaccine therapy was well tolerated, except for what appeared to be GM-CSF-related allergic reactions in 2 patients. Delayed-type hypersensitivity (DTH) tests to irradiated tumor cells were positive in 0 of 20 patients tested at baseline, but converted to positive in 8 patients (40%). At a median follow-up of 13.8 months, there is a 95% overall survival and a 48% progression-free survival. Four (4) patients have already survived more than 3.0 years since starting the vaccine.

CONCLUSION: Based on tolerability, rate of tumor DTH conversion, and encouraging survival, the trial will continue accrual to at least 19 patients with measurable disease and 40 patients who lack measurable disease at the time of treatment.

PMID: 15650459 [PubMed - indexed for MEDLINE]




Anticancer Res. 2003 Mar-Apr;23(2A):969-74.


Adjuvant therapy of renal cell carcinoma patients with an autologous tumor cell lysate vaccine: a 5-year follow-up analysis.

Repmann R, Goldschmidt AJ, Richter A.

Department of Urology, St. Georg Hospital Leipzig, Delitzscher Str. 141, 04129 Leipzig, Germany. repi@surfEU.de

BACKGROUND: Non-metastasized renal cell carcinoma (RCC) is associated with postoperative progression in 1 out of 3 patients. However, no adjuvant therapy after radical nephrectomy has been established. We investigated the impact of an adjuvant autologous tumor cell lysate vaccination on the 5-year survival rates of patients with non-metastasized RCC.

PATIENTS AND METHODS: Between 1990 and 1995, a total of 360 patients with RCC underwent a radical nephrectomy at the St. Georg Hospital Leipzig, Germany. There were 236 patients with RCC stages T2N0M0 or T3N0M0. Out of this group, 148 consecutive patients received an adjuvant autologous tumor cell lysate vaccine (vaccine group, 72 patients with T2N0M0 and 76 patients with T3N0M0), while the remaining 88 patients had no adjuvant therapy (control group, 52 patients with T2N0M0 and 36 patients with T3N0M0). Both groups were comparable for parameters such as age, sex, tumor localization and size, and Störkel-score (p > 0.05 for each parameter; Chi-Square test and Wilcoxon-Mann-Whitney test).

RESULTS: For RCC stage T2N0M0, the 5-year progression-free survival rate in the control group was 65.3% compared to 84.6% in the vaccine group (p = 0.0023, log-rank test). The 5-year overall survival was 71.4% in the control group compared to 86% in the vaccine group (p = 0.0059, log-rank test). Patients with RCC stage T3N0M0 in the vaccine group demonstrated a clear advantage in terms of 5-year overall survival (77.5% vs. 25% in the control group, p < 0.0001, log-rank test) and 5-year progression-free survival (68.2% in the vaccine group vs. 19.4% in the control group, p < 0.0001, log-rank test).

CONCLUSION: Adjuvant autologous tumor cell lysate vaccination may improve the outcome of patients with non-metastasized RCC after radical nephrectomy. A prospective randomized and multicenter phase III trial was started in 1997 to confirm these results.

PMID: 12820332 [PubMed - indexed for MEDLINE] Link





Folia Biol (Praha). 2003;49(2):69-73. Links


Adjuvant autologous tumour cell-lysate vaccine versus no adjuvant treatment in patients with M0 renal cell carcinoma after radical nephrectomy: 3-year interim analysis of a German multicentre phase-III trial.

Doehn Ch, Richter A, Lehmacher W, Jocham D.

Department of Urology, University of Lübeck Medical School, Lübeck, Germany.

Even M0 RCC is associated with tumour progression in approximately 30% of all patients after radical nephrectomy. Nevertheless, no effective adjuvant treatment after radical nephrectomy has been established. In a multicentre phase-III trial we investigated the impact of an adjuvant autologous tumour cell-lysate vaccination on the progression-free survival of patients with M0 RCC after radical nephrectomy. Between January 1997 and August 1998 a total of 558 patients with a renal tumour were enrolled at 55 different centres (study group) in Germany. Prior to radical nephrectomy all patients were centrally randomized (Quintiles Germany) to either receive an adjuvant autologous tumour cell-lysate vaccine (6 applications at 4-week intervals after radical nephrectomy) or to receive no adjuvant treatment (control group) after radical nephrectomy. All patients were evaluated following standardized diagnostic investigations at 6-month intervals. Following the inclusion criteria (RCC stages pT2-3bpN0-3M0, TNM-classification, UICC 1993), 365 patients were evaluable for the 3-year progression-free survival analysis. There were 240 patients with stage pT2pN0M0 (104 in the vaccine group and 136 patients in the control group) and 89 patients with stage pT3pN0M0 (46 in the vaccine group and 43 patients in the control group). The remaining 36 patients had positive lymph nodes. The trial was performed according to ICH-GCP guidelines.

The 3-year progression-free survival rate for all tumour stages was 84.7% in the vaccine group and 80.9% in the control group.

Patients with RCC stage pT3pN0-3M0 in the vaccine group demonstrated an advantage (74.4% in the vaccine group vs 65.9% in the control group). For RCC stage pT2pN0-3M0 the 3-year progression-free survival rate in the vaccine group was 89.7% compared to 85.7% in the control group. Follow-up of all patients enrolled in this trial is ongoing. This is the first randomized trial indicating a benefit from an adjuvant vaccination in patients with M0 RCC after radical nephrectomy. The advantage in terms of progression-free survival was more pronounced in patients with T3-tumours. However, it must be emphasized that the results of the final study report (2003) must be awaited before definite recommendations can be made.

PMID: 12779015 [PubMed - indexed for MEDLINE] Link




Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial.

Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C.

Department of Urology, University of Lübeck Medical School, Ratzeburger Allee 160, 23538 Lübeck, Germany. Prof.Jocham.MUL@t-online.de

BACKGROUND: Organ-confined renal-cell carcinoma is associated with tumour progression in up to 50% of patients after radical nephrectomy. At present, no effective adjuvant treatment is established. We aimed to investigate the effect of an autologous renal tumour cell vaccine on risk of tumour progression in patients with stage pT2-3b pN0-3 M0 renal-cell carcinoma.

METHODS: Between January, 1997, and September, 1998, 558 patients with a renal tumour scheduled for radical nephrectomy were enrolled at 55 institutions in Germany. Before surgery, all patients were centrally randomised to receive autologous renal tumour cell vaccine (six intradermal applications at 4-week intervals postoperatively; vaccine group) or no adjuvant treatment (control group). The primary endpoint of the trial was to reduce the risk of tumour progression, defined as progression or death. All patients were assessed after standardised diagnostic investigations at 6-month intervals for a minimum of 4.5 years.

FINDINGS: By preoperative and postoperative inclusion criteria, 379 patients were assessable for the intention-to-treat analysis. At 5-year and 70-month follow-up, the hazard ratios for tumour progression were 1.58 (95% CI 1.05-2.37) and 1.59 (1.07-2.36), respectively, in favour of the vaccine group (p=0.0204, log-rank test). 5-year and 70-month progression-free survival rates were 77.4% and 72%, respectively, in the vaccine group and 67.8% and 59.3%, respectively, in the control group. The vaccine was well tolerated, with only 12 adverse events associated with the treatment.

INTERPRETATION: Adjuvant treatment with autologous renal tumour cell vaccine in patients with renal-cell carcinoma after radical nephrectomy seems to be beneficial and can be considered in patients undergoing radical nephrectomy due to organ-confined renal-cell carcinoma of more than 2.5 cm in diameter.

PMID: 14987883 [PubMed - indexed for MEDLINE]