In a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor ...cell vaccines (TCV). Both vaccines presented antigens from cell-renewing autologous tumor cells. The current analysis was performed to better understand the immune responses induced by these vaccines, and their association with survival.
110 proteomic markers were measured at a week-0 baseline, 1 week before the first of 3 weekly vaccine injections, and at week-4, 1 week after the third injection. Data was presented as a deviation from normal controls. A two-component principal component (PC) statistical analysis and discriminant analysis were performed on this data set for all patients and for each treatment cohort.
At baseline PC-1 contained 64.4% of the variance and included the majority of cytokines associated with Th1 and Th2 responses, which positively correlated with beta-2-microglobulin (B2M), programmed death protein-1 (PD-1) and transforming growth factor beta (TGFβ1). Results were similar at baseline for both treatment cohorts. After three injections, DCV-treated patients showed correlative grouping among Th1/Th17 cytokines on PC-1, with an inverse correlation with B2M, FAS, and IL-18, and correlations among immunoglobulins in PC-2. TCV-treated patients showed a positive correlation on PC-1 among most of the cytokines and tumor markers B2M and FAS receptor. There were also correlative changes of IL12p40 with both Th1 and Th2 cytokines and TGFβ1. Discriminant analysis provided additional evidence that DCV was associated with innate, Th1/Th17, and Th2 responses while TCV was only associated with innate and Th2 responses.
These analyses confirm that DCV induced a different immune response than that induced by TCV, and these immune responses were associated with improved survival. Trial registration Clinical trials.gov NCT004936930 retrospectively registered 28 July 2009.
A promising personal immunotherapy is autologous dendritic cells (DC) loaded ex vivo with autologous tumor antigens (ATA) derived from self-renewing autologous cancer cells. DC-ATA are suspended in ...granulocyte-macrophage colony stimulating factor at the time of each subcutaneous injection. Previously, irradiated autologous tumor cell vaccines have produced encouraging results in 150 cancer patients, but the DC-ATA vaccine demonstrated superiority in single-arm and randomized trials in metastatic melanoma. DC-ATA have been injected into more than 200 patients with melanoma, glioblastoma, and ovarian, hepatocellular, and renal cell cancers. Key observations include: 1 greater than 95% success rates for tumor cell cultures and monocyte collection for dendritic cell production; 2 injections are well-tolerated; 3 the immune response is rapid and includes primarily TH1/TH17 cellular responses; 4 efficacy has been suggested by delayed but durable complete tumor regressions in patients with measurable disease, by progression-free survival in glioblastoma, and by overall survival in melanoma.
Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) ...Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.
Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.
Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.
AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.
NCT, NCT03400917 , Registered 10 January 2018.
This report describes efforts to understand the immune mechanism of action that led to a complete response in a patient with progressive, refractory, metastatic melanoma after treatment with a ...therapeutic vaccine consisting of autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from cells that were self-renewing in cell culture. Her histocompatibility type proved to be HLA B27 with extensive mutations in the HLA-A locus. Exomic analysis of proliferating tumor cells revealed more than 2800 non-synonymous mutations compared to her leukocytes. Histology of resected tumor lesions showed no evidence of an existing or suppressed immune response. In in vitro mixed cell cultures, DC loaded with ATA induced increased IL-22 expression, and a four-fold increase in CD8 + T lymphocytes. Cryopreserved blood samples obtained at week-0, 1 week before the first of three-weekly vaccine injections, and at week-4, 1 week after the third dose, were analyzed by protein array and compared for 110 different serum markers. At baseline, she had marked elevations of amyloid A, IL-12p40, IL21, IL-22, IL-10, IL-16, GROa, TNF-alpha, IL-3, and IL-2, and a lesser elevation of IL-15. One week after 3 weekly vaccinations she had a further 80% increase in amyloid A, a further 66% increase in IL-22, a 92% decrease in IL12p40, a 45% decrease in TGF-β and 26% decrease in IL-10. The data suggested that by 3 weeks after the first DCV injection, vaccine-induced changes in this particular patient were most consistent with enhanced innate and Th1 immune responses rather than Th2 or Th17.
Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from ...each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA.
Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections.
Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to > 60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio = 0.304, p = 0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination.
This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine.
Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009.
BackgroundPersonal therapeutic cancer vaccines consisting of autologous dendritic cells (DC) loaded ex vivo with autologous tumor antigens (ATA) derived from cells that are self-renewing in culture ...(cancer-initiating cells, stem cells) have been clinically tested for more than 20 years. The current study addressed feasibility, safety, and efficacy of the DC-ATA approach.MethodsATA, as irradiated tumor cells (ITC) or ITC lysates, were derived from short-term tumor cell lines established from resected cancer tissue. Peripheral blood monocytes (MC) were collected by leukapheresis; MC were differentiated into DC by culturing with interleukin-4 and granulocyte-macrophage colony-stimulating-factor (GM-CSF). Cryopreserved doses were thawed, suspended in 500 mcg GM-CSF, and injected at weeks 1, 2, 3, 8, 12, 16, 20, and 24. Data was derived from clinical trials conducted during 2000–2023 in patients with metastatic renal, hepatocellular, and ovary cancers, melanoma, and glioblastoma (GBM). Key end-points were DC-ATA manufacturing success rates, treatment emergent adverse events (TEAE), objective response rates, progression-free survival (PFS) and overall survival (OS).ResultsThe success rate for establishing tumor cell lines in proprietary stem cell media was 173/178 (97.2%) including 80/82 GBM, 73/75 ovary, 17/18 liver, 3/3 other. During 2002–2023, leukapheresis procedures yielded sufficient monocytes in 218/223 patients (97.8%) including 74/74 melanoma, 72/74 GBM, 50/53 ovary, 11/11 renal cell, 8/8 hepatoma, and 3/3 other. Of 187 treated patients, no one discontinued DC-ATA because of TEAE; there were no grade 4 TEAE. Most common TEAE were mild to moderate, self-limited local injection site reactions and flu-like symptoms. There was no difference in TEAE frequency or grade in a blinded, randomized trial of DC-ATA vs MC in ovary patients. Immune responses were more favorable for DC-ATA vs ITC in metastatic melanoma, and for DC-ATA vs MC in advanced ovary cancer. During treatment there were no objective responses among 30 patients with measurable metastatic disease, but 3 (10%) had delayed, durable, complete remissions (2 renal, 1 melanoma). In GBM PFS of 10.4 months was 50% longer than in standard treatment arms of six randomized trials. In metastatic melanoma DC-ATA was associated with better OS compared to historical treatment with ITC vaccine (median 60 vs 20.4 months, p<0.001), and better OS compared to ITC in a randomized trial (43.4 vs 20.5 months with a 70% reduction in death p=0.0053)ConclusionsThis DC-ATA approach is feasible and reproducible across tumor types, treatment is well-tolerated, and there is efficacy in some patients. Additional investigation is warranted.Trial RegistrationClinicaltrials.gov: NCT00014131, NCT00012064, NCT00436930, NCT00331526, NCT03400917Ethics ApprovalAll clinical studies obtained approvals from local ethics committees or institutional review boards, and all participants gave written informed consent.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a world-wide pandemic. Internationally, because of availability, accessibility, and distribution issues, there is a need for ...additional vaccines. This study aimed to: establish the feasibility of personal dendritic cell vaccines to the SARS-CoV-2 spike protein, establish the safety of a single subcutaneous vaccine injection, and determine the antigen-specific immune response following vaccination. In Phase 1, 31 subjects were assigned to one of nine formulations of autologous dendritic cells and lymphocytes (DCL) incubated with 0.10, 0.33, or 1.0 µg of recombinant SARS-CoV-2 spike protein, and admixed with saline or 250 or 500 µg of granulocyte-macrophage colony-stimulating factor (GM-CSF) prior to injection, then assessed for safety and humoral response. In Phase 2, 145 subjects were randomized to one of three formulations defined by incubation with the same three quantities of spike protein without GM-CSF, then assessed for safety and cellular response. Vaccines were successfully manufactured for every subject at point-of-care. Approximately 46.4% of subjects had a grade 1 adverse event (AE); 6.5% had a grade 2 AE. Among 169 evaluable subjects, there were no acute allergic, grade 3 or 4, or serious AE. In Phase 1, anti-receptor binding domain antibodies were increased in 70% of subjects on day-28. In Phase 2, in the 127 subjects who did not have high levels of gamma interferon-producing cells at baseline, 94.4% had increased by day 14 and 96.8% by day 28. Point-of-care personal vaccine manufacturing was feasible. Further development of such subject-specific vaccines is warranted.
Administering dendritic cells (DC) loaded with tumor-associated antigens (TAA)
is a promising strategy for therapeutic vaccines in advanced melanoma. To date the induction of immune responses to ...specific TAA has been more impressive than clinical benefit because of TAA limitations, suboptimal DC and possibly immune-checkpoint inhibition. Various products, antigen-loading techniques, treatment schedules, routes of administration and adjunctive agents continue to be explored. Biologic heterogeneity suggests autologous tumor as the optimal TAA source to induce immune responses to the entire repertoire of unique patient-specific neoantigens. Many questions remain regarding the optimal preparation of DC and strategies for antigen loading. Effective DC vaccines should result in additive or synergistic effects when combined with checkpoint inhibitors.
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