EXTH-44. SYSTEMIC CCL3 TREATMENT ENHANCES IMMUNOTHERAPY EFFICACY THROUGH IMPROVED DENDRITIC CELL MIGRATION

Abstract INTRODUCTION Dendritic cell (DC) vaccines have shown marginal success in treating glioblastoma (GBM), with inefficient vaccine migration a major limitation. Prior evidence from our clinical trials demonstrated that tetanus diphtheria (Td) preconditioning produced greater DC migration to vaccine draining lymph nodes (VDLNs) and long-term survival. Greater DC numbers reaching VDLNs was also associated with long-term survival. We found from preclinical studies and our patients that increased DC migration was dependent upon the chemokine (C-C motif) ligand 3 (CCL3). METHODS The effect of systemic CCL3 treatment on DC vaccine migration (n=5), antigen-specific T cell responses (n=5) and efficacy against orthotopic GL261-OVA and SMA560 tumors (n=10) was studied in C57Bl/6 and VMdK mice. DCs were electroporated with OVA-mRNA or pulsed with ODC1 neoantigen peptide. Median overall survival (mOS) was measure in days (d) post-intracranial implantation. RESULTS Intravenous CCL3 at the time of intradermal DC vaccination resulted in a dose-dependent increase in migration to VDLN (10ug p=0.036, 20ug p< 0.0001, 50ug p< 0.0001). Mean migration levels following CCL3 treatment were similar to Td-preconditioning (p=0.52) but showed significantly less variability between mice. Combined CCL3 and DC vaccination generated more tumor antigen-specific CD8+IFNγ+ T cells 7 days compared to DC vaccine alone (p=0.0045). CCL3+OVA-DC treatment resulted in significantly greater survival compared to OVA-DC alone (mOS 37 vs 19.5 d; p=0.0174) in established GL261-OVA. CCL3 treatment increased survival in mice with established SMA560 tumors treated with neoantigen ODC1 peptide-pulsed DCs (Tumor alone mOS: 21d, DCvac: 25d, CCL3+DCvac: 48d, p=0.002). CONCLUSIONS These data combined with previous success of our DC vaccine clinical trials reflect the potency of CCL3 to enhance DC vaccine-specific migration, immune responses and survival. CCL3 is a novel and safe adjuvant to overcome prior limitations in DC vaccine therapy and may be translatable to increase heterogeneous tumor antigen presentation following vaccine-targeted tumor killing.

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Long-term survival in patients with metastatic melanoma vaccinated with melanoma-antigen loaded dendritic cells

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8547 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8547-8547

Author(s):

J. W. Fay ◽

J. Banchereau ◽

K. Palucka

Keyword(s):

Clinical Trials ◽

Dendritic Cells ◽

Metastatic Melanoma ◽

Term Survival ◽

Melanoma Antigen ◽

Dc Vaccine ◽

Positron Emission ◽

Dc Vaccines ◽

Clinical Responses

8547 Background: Previous clinical trials have demonstrated safety and tolerability of cancer antigen-loaded dendritic cells (DCs) in the treatment of metastatic melanoma. Further, DCs administered to patients with metastatic melanoma are immunogenic and induce durable clinical responses even in patients who failed previous cytotoxic therapy. This report is an analysis of long term clinical outcomes of DC vaccinated patients from our institution. Methods: Between March 1999 and February 2005 seventy patients with metastatic melanoma were treated with DC vaccines in four sequential phase I-IIa clinical trials. Most patients had M1b or M1c metastatic disease. DCs were generated either from CD34+ hematopoietic progenitors or from monocytes. Forty nine HLA-A*0201+ patients received vaccines pulsed with melanoma antigen derived peptides (MART-1, MAGE-3, TYR and gp100). Twenty one patients received DCs loaded with killed allogeneic melanoma cells. KLH was used as helper antigen and, in HLA-A*0201+ patients, Flu-Matrix peptide was used as control antigen. Patients received up to eight DC vaccinations over a maximum of 7 months. Results: DC vaccinations were safe and tolerable. Fifteen out of 70 (21%) patients are alive as of November 2006. The median survival in this group of surviving patients is 46 months (range 22–92 months). Three patients had no evidence of disease upon completion of DC vaccinations by clinical and positron emission tomography scanning. Four patients had experienced objective clinical responses by RECIST criteria (2 CRs and 2 PRs) based on clinical examination and computerized tomography or magnetic resonance imaging. These included two patients that had failed previous cytotoxic and cytokine therapy. Eight patients are alive with disease. Five of 15 long term survivors had no additional therapy other than DC vaccinations including a patient with CR of liver lesions who remains free of disease 80 months post DC vaccination. Conclusions: DC vaccines bring clinical benefit and elicit durable responses in a fraction of patients with metastatic melanoma. These vaccines may provide a survival advantage. Future studies are underway to improve DC vaccine efficacy for treatment of metastatic melanoma. No significant financial relationships to disclose.

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Long-term survival of patients with carcinoid syndrome in clinical trials of telotristat ethyl

Annals of Oncology ◽

10.1093/annonc/mdx368.014 ◽

2017 ◽

Vol 28 ◽

pp. v147-v148 ◽

Cited By ~ 1

Author(s):

P. Lapuerta ◽

M.H. Kulke ◽

M. Caplin ◽

E. Bergsland ◽

L. Anthony ◽

...

Keyword(s):

Clinical Trials ◽

Carcinoid Syndrome ◽

Term Survival ◽

Long Term Survival

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Long-term survival of pancreatic cancer patients treated with multimodal therapy combined with WT1-targeted dendritic cell vaccines

Human Vaccines & Immunotherapeutics ◽

10.1080/21645515.2018.1524238 ◽

2018 ◽

Vol 15 (2) ◽

pp. 397-406 ◽

Cited By ~ 3

Author(s):

Shuichi Hanada ◽

Tomoko Tsuruta ◽

Kouichi Haraguchi ◽

Masato Okamoto ◽

Haruo Sugiyama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dendritic Cell ◽

Cancer Patients ◽

Multimodal Therapy ◽

Term Survival ◽

Long Term Survival ◽

Dendritic Cell Vaccines

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Long-term survival of patients suffering from solid extra-cranial neoplasias after dendritic cell-based cancer immune therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.3096 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 3096-3096

Author(s):

Friedrich Erhart ◽

Thomas Felzmann ◽

Philipp Funovics ◽

Wolfgang Holter ◽

Leo Kager ◽

...

Keyword(s):

Dendritic Cell ◽

Immune Therapy ◽

Term Survival ◽

Long Term Survival

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Loss of patients in clinical trials that measure long-term survival following myocardial infarction

Controlled Clinical Trials ◽

10.1016/0197-2456(86)90029-2 ◽

1986 ◽

Vol 7 (2) ◽

pp. 134-148 ◽

Cited By ~ 9

Author(s):

Rohit Bhaskar ◽

Dinah Reitman ◽

Henry S. Sacks ◽

Harry Smith ◽

Thomas C. Chalmers

Keyword(s):

Myocardial Infarction ◽

Clinical Trials ◽

Term Survival ◽

Long Term Survival

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Margin Clearance and Outcome in Resected Pancreatic Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.5104 ◽

2009 ◽

Vol 27 (17) ◽

pp. 2855-2862 ◽

Cited By ~ 210

Author(s):

David K. Chang ◽

Amber L. Johns ◽

Neil D. Merrett ◽

Anthony J. Gill ◽

Emily K. Colvin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trials ◽

Adjuvant Radiotherapy ◽

Resection Margin ◽

Resection Margins ◽

Term Survival ◽

Long Term Survival ◽

Operative Resection ◽

Occult Metastatic Disease

Purpose Current adjuvant therapies for pancreatic cancer (PC) are inconsistently used and only modestly effective. Because a high proportion of patients who undergo resection for PC likely harbor occult metastatic disease, any adjuvant trials assessing therapies such as radiotherapy directed at locoregional disease are significantly underpowered. Stratification based on the probability (and volume) of residual locoregional disease could play an important role in the design of future clinical trials assessing adjuvant radiotherapy. Patients and Methods We assessed the relationships between margin involvement, the proximity to operative resection margins and outcome in a cohort of 365 patients who underwent operative resection for PC. Results Microscopic involvement of a resection margin by tumor was associated with a poor prognosis. Stratifying the minimum clearance of resection margins by 0.5-mm increments demonstrated that although median survival was no different to clear margins based on these definitions, it was not until the resection margin was clear by more than 1.5 mm that optimal long-term survival was achieved. Conclusion These data demonstrate that a margin clearance of more than 1.5 mm is important for long-term survival in a subgroup of patients. More aggressive therapeutic approaches that target locoregional disease such as radiotherapy may be beneficial in patients with close surgical margins. Stratification of patients for entry onto future clinical trials based on this criterion may identify those patients who benefit from adjuvant radiotherapy.

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Long-term survival of patients with carcinoid syndrome in clinical trials of telotristat ethyl

Endocrine Abstracts ◽

10.1530/endoabs.52.p22 ◽

2017 ◽

Author(s):

Pablo Lapuerta ◽

Matthew Kulke ◽

Martyn Caplin ◽

Emily Bergsland ◽

Lowell Anthony ◽

...

Keyword(s):

Clinical Trials ◽

Carcinoid Syndrome ◽

Term Survival ◽

Long Term Survival

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Ten Year-Long Term Survival After up-Front Autologous Stem Cell Transplantation in Multiple Myeloma: Results From Two Prospective Clinical Trials

Blood ◽

10.1182/blood.v120.21.594.594 ◽

2012 ◽

Vol 120 (21) ◽

pp. 594-594

Author(s):

Elena Zamagni ◽

Francesco Di Raimondo ◽

Francesca Patriarca ◽

Patrizia Tosi ◽

Annalisa Pezzi ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Regression Analysis ◽

Stem Cell ◽

High Quality ◽

Term Survival ◽

Long Term Survival ◽

Long Term Survivors

Abstract Abstract 594 Survival of patients with multiple myeloma (MM) has been extended with the introduction of autologous stem cell transplantation (ASCT). More recently, availability of highly effective novel agents has further improved patient outcomes. However, it is still the matter of debate whether a proportion of patients treated with ASCT can enjoy a long term survival, while sustaining prolonged high quality response. To address this issue and to identify those variables which were related to long-term survival, we performed a post-hoc analysis of two large prospective clinical trials of ASCT in newly diagnosed MM patients, the first one comparing single versus double ASCT and the second one incorporating thalidomide-dexamethasone (TD) into double ASCT. A total of 321 patients were randomly assigned in the first study to receive either a single or double ASCT, as previously described (Cavo M et al, JCO 2007). Three hundred and fifty seven patients were enrolled in the subsequent multicenter phase 2 study incorporating TD from the outset until the second ASCT; details of the protocol were previously reported (Cavo et al, J. Clin. Oncol 2009). Results were updated as of 30 March 2012 and compared with those previously reported. All the analyses were performed on an intention-to-treat basis. After a median follow-up of 61 months for the entire treatment population of the first study, PFS remained significantly longer with tandem versus single ASCT (median 37 vs 25 months, P= 0.012), while OS was similar in the two groups (median 71 vs 67 months). 47% and 33% of the patients in the double and single ASCT group achieved a CR+nCR (P= 0.008). Overall, in 24% and 11% of the patients, CR+nCR was sustained for more than 5 and 10 years, respectively. In a multivariate Cox regression analysis, best response (CR+nCR) ever achieved was the most important variable significantly extending PFS (P= 0.003) and OS (P=0.050); random assignment to double ASCT was an additional variable predicting for prolonged PFS(P= 0.026). After a median follow-up of 84 months from starting TD in the second study, median values of PFS and OS were 47.2 and 109.6 months, respectively. The final rate of CR+nCR was 34%, which was maintained for a median of 53 months. Overall, in 42.1% and 9.1% of the patients CR+nCR was sustained for more than 5 and 8 years, respectively. On multivariate analysis, failure to ever achieve at least CR+nCR, low Hb, high β2-m and t(4;14)±del(17p) were found to be independent variables predicting for poorer outcomes. In particular, a shorter OS was seen for patients ever lacking high-quality responses (HR: 0.35, 0.23–0.54, p<0.0001) and with t(4;14)±del(17p) (HR: 0.51, 0.33–0.79, p=0.0030). Overall, 23% and 20% of patients in the first and second study were alive over 10 or 8 years, respectively (long-term survivors). Median PFS of long-term survivors in the 2 studies were 74 and 87.7 months, respectively, versus 25 and 37 months for the rest of the population (P= 0.0000). Median duration of CR+nCR were 70 and 78 months in the long-term survivors group for the first and second study, respectively, in comparison with 21 and 49 months in the remaining patients (P<0.001 for both). The 10 and 8-year estimates of OS after relapse or progression in the long-term survivors of the two protocols were 58% and 72%, respectively, in comparison to a median value of 24 and 23 months for the control group (p<0.0001 for both). In a logistic regression analysis, attainment of high-quality responses was independently associated with long-term survival in both the studies (first study: OR: 1.8, 1.06–3.01, P= 0.03; second study: OR: 4.3, 2.17–8.60, P= 0.000). In conclusion, although the comparison between TD incorporated into ASCT and ASCT without thalidomide was not directly addressed by this analysis, TD + ASCT was associated with extended PFS and OS. Approximately 20% of the patients undergoing up-front ASCT can achieve long term survival (8–10 years from start of treatment), with 33% of them remaining relapse free. Attainment of sustained high-quality responses was the leading independent variable predicting for long-term OS. Prolonged survival after relapse was a contributing factor to long-term OS. Disclosures: Off Label Use: One of the 2 protocols discussed includes the use of thalidomide as induction prior to ASCT.

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