scholarly journals CTIM-33. PHASE II TRIAL OF VACCINE IMMUNOTHERAPY IN PRIMARY GLIOBLASTOMA: ADJUNCTIVE AUTOLOGOUS DENDRITIC CELLS PULSED WITH LYSATE FROM IRRADIATED SELF-RENEWING AUTOLOGOUS TUMOR CELLS (AV-GBM-1)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi58-vi58
Author(s):  
Daniela A Bota ◽  
David E Piccioni ◽  
Christopher M Duma ◽  
Renato V LaRocca ◽  
Santosh Kesari ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Phase Ii ◽  
Tumor Antigens ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Autologous Tumor ◽  
Lipocalin 2 ◽  
Primary Glioblastoma ◽  
Gm Csf ◽  
Post Surgery

Abstract In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age < 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS > 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development. Clinicaltrials.gov NCT03400917.

Patient-specific vaccines derived from proliferating autologous tumor cell lines and dendritic cells: Results of a phase II trial in metastatic melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8555-8555
Author(s):  
R. O. Dillman ◽  
S. R. Selvan ◽  
P. M. Schiltz ◽  
C. DePriest ◽  
C. Peterson ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Metastatic Melanoma ◽  
Tumor Cells ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Delayed Type Hypersensitivity ◽  
Patient Specific ◽  
Autologous Tumor ◽  
Gm Csf ◽  
Measurable Disease

8555 Background: Patient-specific vaccines utilizing proliferating tumor cells, or tumor stem cells, may be the ideal products for active specific immunotherapy. Methods: Eligible patients had recurrent or metastatic melanoma from which a cell line was established, expanded to 200 million cells, incubated with interferon-gamma, irradiated and cryopreserved. Autologous dendritic cells (DC) were derived from peripheral blood mononuclear cells cultured in IL-4 and GM-CSF. DC were incubated with the irradiated tumor cells, then cryopreserved in 20- million-cell aliquots, which were thawed, washed and suspended in 500 micrograms of GM-CSF for injection. Treatment consisted of s.c. injections weekly × 3, then monthly × 5 in a 2-stage phase II trial with two stratifications. Patients were characterized as having objectively measurable disease (OMD) or non-measurable disease (NMD). Plans were to enroll 30 to 80 patients: 15 to 40 with OMD, 15 to 40 with MD. Objectives were to determine safety, frequency of conversion of delayed type hypersensitivity (DTH) reactions to irradiated autologous tumor cells, objective response rate (ORR) using RECIST criteria, progression-free survival (PFS), overall survival (OS), and comparison to a historical control group. Results: Between January 2001 and April 2006, 55 patients were enrolled; 53 were eligible and evaluable. The 30 men and 23 women had a median age of 50 years; 15 had OMD and 38 NMD. Patients received an average of 7.4 vaccinations out of a possible 8. Treatment was well- tolerated. 25% had a positive tumor DTH test: 1 at baseline, 7 after 3 injections, 5 after 8 injections. ORR was 0/15. Follow up for the 39 surviving patients ranges from 7 to 67 months with a median of 30 months. Median PFS is 7.1 months with 24 patients remaining progression-free. Only 14 patients have died; median OS has not been reached. 5-year projected survival is 70%; 20 patients are alive 2.5 to 5.5 years from start of vaccine. OS is better than observed for 48 comparable patients that we treated previously in a trial with irradiated tumor cells without DC (p=0.016). Conclusion: This patient-specific vaccine approach is feasible, safe, associated with encouraging survival, and warrants further investigation. No significant financial relationships to disclose.

scholarly journals 332 Tumor collection and establishment of tumor-initiating cell cultures as antigen source for AV-GBM-1 dendritic cell vaccines for a phase II trial in patients with newly diagnosed glioblastoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A358-A358
Author(s):  
Christopher Duma ◽  
Daniela Bota ◽  
Frank Hsu ◽  
David Piccioni ◽  
Renato LaRocca ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Phase Ii ◽  
Tumor Antigens ◽  
Patient Specific ◽  
Autologous Tumor ◽  
Newly Diagnosed ◽  
Tumor Initiating Cells ◽  
Eligibility Criteria ◽  
Primary Glioblastoma ◽  
Dendritic Cell Vaccines

BackgroundDespite standard aggressive therapy (maximum safe surgical resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ), then maintenance TMZ), 2-year survival is only about 25% for patients with newly diagnosed primary glioblastoma (GBM). Adding AV-GBM-1, a vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve survival. One objective of a multi-center phase II clinical trial was to determine the feasibility of collecting fresh GBM and establishing short-term cell cultures of GBM tumor-initiating cells (TIC) to serve as ATA source.MethodsKey eligibility criteria for tumor collection were (1) clinical suspicion of new primary GBM, (2) age 18 to 70 years (3) tentative agreement to undergo a leukapheresis procedure after recovery from surgery, and (4) tentative plans for RT/TMZ. Fresh tumor was placed in media and shipped in a transport kit by overnight courier to AIVITA where a cell suspension was placed in culture and incubated in serum-free medium with factors that favor survival and proliferation of TICS (stem cells and early progenitor cells). The intent was to produce a patient-specific DC-ATA vaccine by incubating a lysate of irradiated TICs with autologous DC for subsequent subcutaneous injection.ResultsPatients were enrolled from five sites in California, one in Kentucky and one in New Jersey. Tumors were collected between August 2018 and January 2020. 106 patients consented for tumor collection, but 15 were not GBM, 4 had insufficient tissue to send, 2 patients withdrew consent, 4 were ineligible because of age, and 1 was ineligible because of autoimmune disease. Of the 80 GBM tumors that were placed into culture, 7 were discontinued because of patient withdrawal. 71/73 (97%) resulted in a successful cell culture; two were unsuccessful because of contamination. 60/71 subsequently consented for intent-to-treat ; 46/60 (77%) had cells in culture for 28 days or less, 11 were in culture for 30 to 35 days, and the remaining 3 were cultured 46, 54, and 55 days. The average number of cells per culture at the time of irradiation was 14.0 million (range 0.78 to 63.3 million). 58/60 (97%) yielded more than 1 million TICs for irradiation for the tumor cell lysate; 36/60 (60%) had more than 10 million cells irradiated. 57 patients were subsequently treated with AV-GBM-1 after recovery from RT/TMZ.ConclusionsSelf-renewing GBM TIC cultures can be reliably and rapidly established for use as the antigen source for personal DC-ATA vaccines.Trial RegistrationClinicaltrialsgov NCT03400917Ethics ApprovalThis study was approved by the Western IRB, approval number 20182582; all participants gave written informed consent before taking part

Chemo-immunotherapy regimen with gemcitabine + FOLFOX 4 (GOLF) followed by subcutaneous (sc) granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). Results from a multicenter phase II trial in colon carcinoma patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3587-3587
Author(s):  
P. Correale ◽  
C. Remondo ◽  
F. Montagnani ◽  
M. S. Rotundo ◽  
S. Marsili ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Colon Carcinoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Phase Iii ◽  
Immunological Study ◽  
Gm Csf ◽  
Anti Tumour Activity ◽  
Tumour Activity

3587 We have recently described a poly-chemotherapy (GOLF) regimen that: A) is active in colon carcinoma patients as second line of therapy; B) induces high levels of necrosis and apoptosis in colon cancer cells; C) up-regulates the expression and release of heat shock proteins (HSP)-70 and -90 and tumour-associated antigens (2,3); and D) down-regulates tumour cell resistance to the death signals of cytotoxic-T-lymphocytes.These effects represented the rationale for projecting GOLFIG regimen. Here we describe the results of a multi-center translational phase II trial designed to evaluate the toxicity, anti-tumour activity of a novel regimen designated as GOLFIG-1, composed by the GOLF poly-chemotherapy followed by the subcutaneous (sc.) administration of GM-CSF and low-dose IL-2 in colorectal carcinoma patients. The study involved 37 patients (21M and 16F, mean age 62.5 years), 24 of whom had received a previous line of treatment, and 24 had liver involvement. All the patients received biweekly chemotherapy with gemcitabine (1g/m2, day 1 and 15), oxaliplatin (85 mg/m2, day 2 and 16), levo-folinic acid (100 mg /m2, day 1, 2, 15, 16) and 5-Fluorouracil (400 mg/m2 as a bolus, and 800 mg/m2 as 24 hour infusion, days 1, 2, 15, 16). These patients also received sc GM-CSF (100 μg, day 3 to 8) followed by sc IL-2 (0.5 X 106 IUs twice a day from day 9 to 14 and from 17 to 29). The treatment was well tolerated and very active in colon carcinoma patients, with high objective response (64.9%) and disease control rates (97.3%), with an average time to progression of 12.94 months (CI 95%: 9.98–15.91). An immunological study confirmed the immunological response to colon carcinoma antigen, a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25+T-reg) and a significant reduction of VEGF levels reported in a previous study. In conclusion, these results suggest that the GOLFIG regimen exerts strong immunological and anti-tumour activity in colorectal cancer patients. A randomized phase III trials aimed to compare the efficacy of GOLFIG-1 with FOLFOX-4 regimen in patients with advanced colorectal carcinoma is presently ongoing. No significant financial relationships to disclose.

scholarly journals CTIM-26. PATIENT-SPECIFIC DENDRITIC CELL VACCINE (DC-ATA) PULSED WITH ANTIGENS FROM SELF-RENEWING AUTOLOGOUS TUMOR CELLS IN THE TREATMENT OF NEWLY-DIAGNOSED GLIOBLASTOMA: A PHASE II TRIAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii39
Author(s):  
Daniela Bota ◽  
David Piccioni ◽  
R LaRocca ◽  
Christopher Duma ◽  
Santosh Kesari ◽  
...  
Keyword(s):  
Phase Ii ◽  
Tumor Antigens ◽  
Dendritic Cell Vaccine ◽  
Primary Objective ◽  
Patient Specific ◽  
Cell Vaccine ◽  
Autologous Tumor ◽  
Gm Csf ◽  
Newly Diagnosed Glioblastoma ◽  
Intent To Treat

Abstract GBM standard treatment is associated with poor survival. Adjunctive therapy with patient-specific vaccines may improve outcomes by enhancing anti-GBM immune responses. A multi-institutional phase II clinical trial was designed with a primary objective of 75% survival 15 months after intent-to-treat enrollment. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with 500 mcg GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Enrollment has been completed in April 2020 (n=60). Three patients withdrew from the study prior to starting treatment leaving 57 patients for whom data is available. So far 57 patients have received 344 doses; 27 have completed all 8 doses, 11 received fewer than 8 doses at the time they discontinued treatment, 19 are currently in treatment. No patient has discontinued treatment because of toxicity. 9 pt had died and the preliminary 12 months overall survival is 74%. In a preliminary serologic analysis 12 of 16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F) by week-3; 9 of 15 (60%) had a decrease in angiogenesis factors, growth factors, and tumor markers by week-8. Immunologic data for all 55 patients who received at least two injections will be available November 2020. This patient-specific DC-ATA immunotherapy approach is feasible, is associated with changes in serologic markers, and may be increasing intratumor inflammation that may be associated with on-target toxicity and efficacy. A interim survival analysis will be conducted in mid-October 2020, 15 months after the 28th patient was enrolled; results will be available November 2020 [Clinicaltrials.gov NCT03400917].

A phase II trial combining tumor-targeting TP53 gene therapy with gemcitabine/nab-paclitaxel as a second-line treatment for metastatic pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4139-4139
Author(s):  
Chris Poki Leung ◽  
Minal A. Barve ◽  
Ming-Shiang Wu ◽  
Kathleen F. Pirollo ◽  
James F. Strauss ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Tp53 Gene ◽  
Phase Iii ◽  
Published Data ◽  
Line Treatment ◽  
Second Line ◽  
First Line

4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]

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