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

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.

Randomized phase II trial of patient-specific dendritic cell vaccines loaded with autologous tumor antigens versus autologous monocytes in patients with primary advanced ovarian cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS10-TPS10
Author(s):  
Robert O. Dillman ◽  
Lisa Abaid ◽  
Candace Hsieh ◽  
Christopher Langford ◽  
Gabriel I. Nistor
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cell ◽  
Cell Line ◽  
Tumor Antigens ◽  
Tumor Cell Line ◽  
Patient Specific ◽  
Autologous Tumor Cell ◽  
Autologous Tumor ◽  
Primary Therapy ◽  
Newly Diagnosed

TPS10 Background: With standard debulking surgery and combination chemotherapy (adjuvant ± neoadjuvant) the 5-year survival for women with newly diagnosed advanced epithelial ovarian cancer (stage III or IV) is less than 40%. After completion of primary therapy there is an opportunity to introduce an immunotherapy modality in an effort to improve long-term survival. In patients with metastatic melanoma, patient-specific vaccines consisting of autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from a short-term autologous tumor cell line were associated with minimal toxicity and a 5-year survival of 50% in a single arm trial, and more than doubled median survival (43 vs. 20 months) in a randomized trial. Newly diagnosed patients with ovarian cancer might benefit from addition of such patient-specific therapeutic vaccines (DC-ATA) to standard therapy. Methods: This is a double-blind, 2:1 randomized trial comparing adjunctive treatment with DC-ATA to autologous monocytes (MC) in patients with newly diagnosed stage III or IV epithelial cancer of the ovary, fallopian tube, or peritoneum. Patients eligible for randomization are those who have completed or discontinued standard primary therapy, have a Karnofsky performance status ≥70, have an autologous tumor cell line, and have a monocyte product from which DC can be derived. The tumor cell line is derived from fresh tumor; MC are derived from leukapheresis, and MC are converted to DC by incubation with GM-CSF and IL-4. Patients are stratified by whether there is no evidence of disease at completion of primary therapy, and then are randomized, typically 6 to 7 months after tumor collection. Treatment can begin about 4 weeks from randomization. The trial has been open at a single site since mid-November 2017; the first tumor was collected in December. Appropriate tumor samples have been submitted from 11 patients and all 11 have resulted in cell lines. The first patient was randomized in May 2018. As of October 2018 four patients had been randomized and all four had started treatment. Additional clinical sites are being initiated. Clinical trial information: NCT02033616.

scholarly journals 952 Phase II trial of AV-GBM-1: dendritic cell vaccine pulsed with lysate enriched for autologous tumor-initiating cell antigens in the treatment of patients with newly diagnosed glioblastoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A1001-A1001
Author(s):  
Daniela Bota ◽  
David Piccioni ◽  
Christopher Duma ◽  
Renato LaRocca ◽  
Santosh Kesari ◽  
...  
Keyword(s):  
Phase Ii ◽  
Standard Therapy ◽  
Randomized Trials ◽  
Progression Free Survival ◽  
Cell Vaccine ◽  
Autologous Tumor ◽  
Newly Diagnosed ◽  
Eligibility Criteria ◽  
Free Survival ◽  
Gm Csf

BackgroundStandard therapy of glioblastoma (GBM), which includes maximum safe resection, concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ) followed by maintenance TMZ, is associated with poor overall survival (OS). Adding treatment with AV-GBM-1, a vaccine consisting of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) may improve OS. A multi-center phase II clinical trial was conducted to determine feasibility, safety, and efficacy of AV-GBM-1.MethodsKey eligibility criteria for tumor collection were clinical suspicion of newly diagnosed GBM and age 18 to 70 years at the time of surgery. Prior to starting RT/TMZ, key eligibility criteria for intent-to-treat-with-AV-GBM-1 enrollment were: (1) primary GBM confirmed, (2) successful GBM cell culture, (3) collection of sufficient numbers of monocytes (MC) by leukapheresis, (4) Karnofsky Performance Status 70 or greater and (5) plan to treat with concurrent RT/TMZ. AV-GBM-1 was manufactured during RT/TMZ. Interleukin-4 and granulocyte-macrophage colony stimulating factor (GM-CSF) were used to differentiate MC into DC. AV-GBM-1 consists of autologous DC incubated with ATA from the lysate of irradiated GBM cells grown in serum-free media with factors that favor the survival and proliferation of stem cells and early progenitor cells. After recovery from RT/TMZ, over six months patients received up to 8 subcutaneous injections of AV-GBM-1 admixed with 500 μg GM-CSF. The primary objective was to determine if OS was 75% or higher 14.6 months from ITT enrollment, which ended January 2020. The minimum follow-up at the time of analysis was 15.2 months. Secondary endpoints included progression-free survival (PDS) from ITT enrollment and from the first injection.ResultsSuccess rates for cell cultures and sufficient monocyte collections were both 97%. AV-GBM-1 was manufactured for 60/60 (100%). 57 patients received 392 injections; 68% received all 8. The primary adverse events (AE) attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Progression-free survival (PFS) from ITT enrollment is 10.3 months, about 50% longer than reported in four randomized trials with comparable standard therapy arms. PFS from the first injection is 8.3 months, which is 51% and 107% longer than reported in two randomized trials with comparable standard therapy arms. OS was 72% at 12 months, but dropped to 54% at 14.6 months; median OS is 16.0 months.ConclusionsPatent-specific AV-GBM-1 was reliably manufactured and distributed for administration. AV-GBM-1 produced minimal toxicity. PFS was very encouraging but did not translate into OS, perhaps because of discontinuation of treatment after 8 months.Trial Registration[Clinicaltrials.gov NCT03400917]Ethics ApprovalWestern IRB, approval number 20182582Consent n/a

scholarly journals 319 Phase II trial of immunotherapy in primary glioblastoma: antigens from self-renewing autologous tumor cells presented by autologous dendritic cell vaccine

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A345-A345
Author(s):  
Daniela Bota ◽  
David Piccioni ◽  
Christopher Duma ◽  
Renato LaRocca ◽  
Santosh Kesari ◽  
...  
Keyword(s):  
Success Rate ◽  
Cell Line ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Tumor Resection ◽  
Patient Specific ◽  
Cell Vaccine ◽  
Autologous Tumor ◽  
Primary Glioblastoma ◽  
Intent To Treat

BackgroundPrimary glioblastoma (GBM) is associated with poor survival. Adjunctive vaccines may improve survival by inducing or enhancing anti-GBM immune responses.MethodsA multi-institutional phase II clinical trial was conducted with a primary objective of 75% survival 15 months after intent-to-treat enrollment. Key eligibility criteria were: (1) primary GBM diagnosis, (2) age < 70 years at time of tumor resection, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) Karnofsky Performance Status (KPS) > 70 after surgical recovery. Dendritic cells (DC) were differentiated from autologous monocytes, then incubated with autologous tumor antigens (ATA) from the GBM cell line-lysate to produce each patient-specific DC-ATA vaccine. Doses were suspended in 500 mcg granulocyte-macrophage colony-stimulating factor (GM-CSF) at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Patients were enrolled just prior to starting standard concurrent temozolomide (TMZ) and radiation therapy (RT) for the intent-to-treat after recovery from RT/TMZ.ResultsTumors were collected August 2018-January 2020. Cell line success rate was 71/73 (97%); monocyte collection success rate was 63/65 (97%), but 10 patients required a second leukapheresis. Patients were enrolled for in-to-treat October 2018-February 2020. The 60 patients included 42 men and 18 women with median age of 59 years (range of 27–70). Racial make-up was 43 White, 10 Hispanic, 2 Black, 1 Asian and 3 Other. KPS was 100 in 4, 90 in 25, 80 in 17 and 70 in 14 (mean 83.2). MGMT methylation was present in 13, absent in 31, and unknown in 16; IDH mutation was present in 7, absent in 50, and unknown in 3. 57 patients had received 380 doses with 9 still under treatment at time of abstract submission. 32 had completed all 8 doses; 16 had received fewer than 8 doses when they discontinued treatment. No patient discontinued treatment because of toxicity, but 28 have been hospitalized for 53 treatment-emergent central nervous system-related serious adverse events including seizures (15 episodes), falls and/or increased focal weakness (13 episodes), or severe headaches or visual changes (3 episodes).ConclusionsThis patient-specific DC-ATA approach is feasible and may be increasing intratumor inflammation that is associated with on-target efficacy and/or toxicity. An interim survival analysis will be conducted in October 2020, 15 months after the median patient was enrolled; results will be available November 2020 as will immunologic data for 55 patients who received at least two injections.Trial RegistrationClinicaltrials. gov NCT03400917.Ethics ApprovalThe study was approved by UCI IRB, approval number 2018-4148.

scholarly journals Patient-specific dendritic cell vaccines with autologous tumor antigens in 72 patients with metastatic melanoma

2019 ◽  
Vol 6 (2) ◽  
pp. MMT20 ◽  
Author(s):  
Robert O Dillman ◽  
Andrew N Cornforth ◽  
Edward F McClay ◽  
Carol Depriest
Keyword(s):  
Dendritic Cell ◽  
Metastatic Melanoma ◽  
Tumor Antigens ◽  
Patient Specific ◽  
Autologous Tumor ◽  
Dendritic Cell Vaccines

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].

scholarly journals Autologous tumor antigens and boron nanosheet-based nanovaccines for enhanced photo-immunotherapy against immune desert tumors

Nanophotonics ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Zhe Sun ◽  
Taojian Fan ◽  
Quan Liu ◽  
Luodan Huang ◽  
Weibin Hu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Tumor Antigens ◽  
Photoacoustic Imaging ◽  
Metastatic Potential ◽  
Photothermal Effect ◽  
Patient Specific ◽  
Autologous Tumor ◽  
Tumor Vaccines ◽  
Therapeutic Vaccines ◽  
Important Field

Abstract Personalized therapeutic vaccines against immune desert tumors are an increasingly important field in current cancer immunotherapy. However, limitations in neoantigen recognition, impotent immune cells, and a lack of intratumoral infiltrated lymphocytes pose challenges for the cancer vaccines. Resected tumors contain various of patient-specific tumor autoantigens (TA), and its derived photonanovaccines have unique competency to overcome abovementioned barriers. We constructed a novel personalized photonanovaccine (B@TA-R848) with surgically sourced TA modified on two-dimensional boron nanosheets (BNSs) via polydopamine coating and loaded with immune adjuvant R848. B@TA-R848 has good properties of drug delivery and release, photoacoustic imaging, photothermal effect, and biocompatibility. In a mouse triple-negative breast cancer model, B@TA-R848-based photonanovaccine induced effective systemic antitumor immune responses, altered the local tumor microenvironment, and increased the intratumoral infiltration of immune cells. The combined photo immunotherapy could significantly inhibit tumor growth, recurrence, and metastasis. This work develops a novel photonanovaccine for low immunogenicity and high metastatic potential tumors, which is of great significance for exploring the clinical development of personalized tumor vaccines against immune desert tumors.

Randomized phase II 8-arm factorial study of adjuvant dose-dense (dd) temozolomide (TMZ) with permutations of thalidomide (Thal), isotretinoin (CRA), and/or celecoxib (Cel) for newly diagnosed glioblastoma (GBM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2003-2003
Author(s):  
Mark R. Gilbert ◽  
Kenneth R. Hess ◽  
Lore Lagrone ◽  
Morris D. Groves ◽  
Victor A. Levin ◽  
...  
Keyword(s):  
Factorial Design ◽  
Phase Ii ◽  
Standard Of Care ◽  
Hepatic Function ◽  
Newly Diagnosed ◽  
Cytostatic Agents ◽  
Current Standard ◽  
Eligibility Criteria ◽  
Randomized Phase Ii ◽  
The Impact

2003 Background: Concurrent radiation and TMZ followed by 6-12 months of adjuvant TMZ (d 1-5 of a 28d cycle) is the current standard of care for patients with newly diagnosed GBM. The addition of cytostatic or signal transduction agents may enhance efficacy without a significant increase in toxicity. A phase I trial (Neuro-oncology 2009) established the safety of ddTMZ with 2 or 3 of the cytostatic agents. Methods: This randomized phase II study was conducted by the Brain Tumor Trials Collaborative (BTTC) and the MDACC CCOP. The primary objectives: determine if specific cytostatic agents added to ddTMZ alters outcomes (PFS, OS) and compare triplet with doublet therapy. Eligibility criteria: centrally confirmed newly diagnosed GBM, age ≥18, KPS≥60, stable or improved after chemoradiation (pseudoprogression allowed), adequate hematologic, renal and hepatic function. Pts were randomly assigned to 12 treatment cycles (28 d/cycle) in 8 arms: ddTMZ alone (150 mg/m2/day, 7-d on, 7-d off) or TMZ-containing doublet, triplet and quadruplet combinations with Thal, CRA, or Cel. Results: The study enrolled 155 eligible patients from 11/2005 to 9/2010 to the 8 arms of the factorial design. Median age was 53 (18-84) and median KPS, 90 (60-100). Compared with TMZ alone, the TMZ+CRA doublet had worse PFS (10.5, 6.5 mo; p=0.043) and OS (21.2, 11.7 mo; p=0.037). Trends were also seen for worse outcome (PFS, OS) for CRA-containing regimens, improved OS for Cel containing arms and no impact of Thal. A strong trend for OS improvement was seen for triplet compared with doublet regimens (20.1, 17.0 mo; p=0.15), but no difference for PFS. Treatment was well tolerated with expected high rates of grade 3/4 lymphopenia, and overall a modest toxicity rate. Conclusions: The results indicate that the addition of CRA to ddTMZ may be detrimental in patients with newly diagnosed GBM. This study demonstrated the utility of the factorial design in efficiently testing drug combinations, the impact of individual agents in these combinations as well as doublet vs. triplet regimens and supports its utility in testing combinations of targeted agents.

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