Cancer Vaccines: Can They Improve Survival?

Dillman, Robert O.

doi:10.1089/cbr.2014.1805

Cited by 6 publications

(4 citation statements)

References 42 publications

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“…The results in each arm of this randomized trial are quite similar to results previously reported for single arm trials of TCV [ 20 ], and DCV [ 21 ]. The lack of correlation between PFS and OS was also observed in the earlier trials, and has been observed for other immunotherapies that may provide long-lasting immune benefit [ 27 ]. Examples of FDA-approved agents that improved OS but had unimpressive ORR or PFS include sipuleucel-T in prostate cancer, [ 28 ] and ipilimumab in melanoma [ 29 ].…”

Section: Discussionmentioning

confidence: 63%

Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses

Dillman

Cornforth²,

Nistor³

et al. 2018

j. immunotherapy cancer

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BackgroundDespite 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.MethodsShort-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.ResultsForty-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.ConclusionsThis 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.Trial registrationClinical trials.gov NCT00948480 retrospectively registered 28 July 2009.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0330-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 63%

Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses

Dillman

Cornforth²,

Nistor³

et al. 2018

j. immunotherapy cancer

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“…Previously, other vaccines and immunomodulatory antibodies have not shown improvement in PFS: sipuleucel-T and PROSTVAC-VF in prostate cancer and ipilimumab and eltrapuldencel-T in melanoma were associated with no improvement in PFS and response rate, but statistically significant benefit in OS (29). The incidence of activating EGFR and ALK translocations was not evaluated in the trial, as the TKIs targeting the referred mutations were not accessible.…”

Section: Discussionmentioning

confidence: 99%

A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non–Small Cell Lung Cancer Patients

Rodríguez

Popa

Martínez

et al. 2016

Clinical Cancer Research

126

121

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Purpose: EGFR is a well-validated target for patients with non–small cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic cancer vaccine composed of human recombinant EGF conjugated to a carrier protein and Montanide ISA51 as adjuvant. The vaccine is intended to induce antibodies against self EGFs that block EGF–EGFR interaction. Experimental Design: To evaluate overall survival, safety, immunogenicity, and EGF concentration in serum after CIMAvax-EGF, a randomized phase III trial was done in patients with advanced NSCLC. Four to 6 weeks after first-line chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomly assigned to a vaccine group, which received CIMAvax-EGF or a control group, treated with best supportive care. Results: Long-term vaccination was very safe. Most frequent adverse reactions were grade 1 or 2 injection-site pain, fever, vomiting, and headache. Vaccination induced anti-EGF antibodies and decreased serum EGF concentration. In the safety population, median survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the control arm. These differences were not significant according the standard log rank (HR, 0.82; P = 0.100), but according a weighted log rank (P = 0.04) that was applied once the nonproportionality of the HR was verified. Survival benefit was significant (HR, 0.77; P = 0.036) in the per-protocol setting (patients receiving at least four vaccine doses): MST was 12.43 months for the vaccine arm versus 9.43 months for the control arm. MST was higher (14.66 months) for vaccinated patients with high EGF concentration at baseline. Conclusions: Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. Clin Cancer Res; 22(15); 3782–90. ©2016 AACR.

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“…Some of these disappointing clinical results may relate to the products themselves, and especially the TAA being presented, but we also know that the immune system of each patient and the biology of each patient's cancer are important determinants of whether induced or enhanced immune responses can result in clinical benefit. However, several immunotherapy products have been associated with improved overall survival despite lack of a high objective response rate and or a significant impact on progression-free survival [103]. Further clinical investigation of DC vaccines is warranted.…”

Section: Resultsmentioning

confidence: 99%

Dendritic Cell Vaccines for Melanoma: Past, Present and Future

Dillman¹,

Nistor²,

Cornforth³

2016

Melanoma Manag.

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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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Cancer Vaccines: Can They Improve Survival?

Cited by 6 publications

References 42 publications

Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses

Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses

A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non–Small Cell Lung Cancer Patients

Dendritic Cell Vaccines for Melanoma: Past, Present and Future

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