Phase II Trial of Dendritic Cells Loaded with Antigens from Self-Renewing, Proliferating Autologous Tumor Cells as Patient-Specific Antitumor Vaccines in Patients with Metastatic Melanoma: Final Report

Dillman, Robert O.; Selvan, Senthamil R.; Schiltz, Patric M.; McClay, Edward F.; Barth, Neil M.; DePriest, Carol; Leon, Cristina De; Mayorga, C.; Cornforth, Andrew N.; Allen, Kanoe

doi:10.1089/cbr.2008.0599

Cited by 67 publications

(119 citation statements)

References 27 publications

(36 reference statements)

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“…It should be emphasized that clinical response (clinical benefit) is achieved in up to 54% of vaccinated patients when a stable disease is regarded as a satisfactory outcome of immunotherapy rather than treatment failure (4,6,10,11). In any case, it is evident that therapeutic cancer vaccination needs further optimization and individualization of its prescription in order to select cancer patients with the greatest likelihood of achieving clinical benefit.…”

Section: Discussionmentioning

confidence: 99%

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

Dobrovolskiene¹,

Strioga²,

Liudkevičienė³

et al. 2014

AML

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Background. Currently a particular interest is given to specific active cancer immunotherapy (therapeutic cancer vaccination) strategies such as treatment with specially “educated” autologous dendritic cells (DCs). The purpose of these vaccines is to enhance antitumor immune responses against the existing tumor. DC vaccines are composed of tumor antigen-loaded mature DCs, which are produced for each cancer patient individually. However, recent data indicate that there are at least two types of mature DCs – immunogenic, which activate antitumor immune responses, and tolerogenic, which suppress immune responses, thereby interfering with effector mechanisms of protective antitumor immunity. Hence, the aim of our study was to assess the expression of immunogenic and tolerogenic potential-representing markers on the surface of therapeutic DC vaccines generated using two different maturation approaches. Materials and methods. Two different DC maturation approaches were investigated: Cocktail 1, composed of lipopolysaccharide (200 ng/ mL) and interferon-γ (50 ng/mL), and Cocktail 2, composed of IL1β (10 ng/mL), IL-6 (10 ng/mL), TNF-α (10 ng/mL), PGE2 (1 μg/mL). Secretion of two basic cytokines – the immunostimulatory IL-12p70 and the immunosuppressive IL-10 – has also been investigated. Results. We show that a subset of immature DCs expressed tolerogenic markers. Importantly their expression profile considerably differed on mature DCs, depending on the maturation approach used. Conclusions. In particular, our results indicate that Cocktail 1 is superior to Cocktail 2 for the production of clinical-grade therapeutic cancer DC vaccines, both in terms of immunophenotypical attributes of DC tolerogenicity and their cytokine secretory profile.

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Section: Discussionmentioning

confidence: 99%

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

Dobrovolskiene¹,

Strioga²,

Liudkevičienė³

et al. 2014

AML

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“…These approaches have to be tested in randomized trials. There also have been efforts to establish short-term autologous tumor cell cultures to serve as an irradiated tumor cell (ITC) vaccine (TCV) [39], or as a source of TAA for loading onto DC to create autologous DCV [40,41]. As summarized elsewhere, a major challenge with the whole tumor approach is the variability in numbers of cancer cells that are actually derived from a tumor sample, and retention of immunosuppressive cells and cytokines in some procedures [7,8].…”

Section: Autologous Tumor To Generate Therapeutic Vaccinesmentioning

confidence: 99%

“…A 74-patient trial of injected autologous ITCs from short-term cell lines was associated with a 5-year survival rate of 28% [39]. Subsequently, a 54-patient trial of autologous DC loaded with TAA from ITC from a short-term cell line (DCV) was associated with a 5-year survival rate of 50% [40]. This was followed by a randomized trial comparing DCV to TCV with both products admixed with GM-CSF.…”

Section: Autologous Tumor To Generate Therapeutic Vaccinesmentioning

confidence: 99%

An Update on the Relevance of Vaccine Research for the Treatment of Metastatic Melanoma

Dillman¹

2017

Melanoma Manag.

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Past & present r In the past decade, the introduction of effective signal transduction inhibitors and anticheckpoint antibodies has significantly improved the prognosis for patients with metastatic melanoma, but the majority of such patients still die within 5 years. r Vaccine approaches designed to induce immunity to well-characterized melanoma-associated antigens, or to antigens expressed on allogeneic tumor cell lines, have not resulted in approved agents. r Despite the limitations associated with the immunosuppressive tumor microenvironment, there now is one intralesional autologous vaccine that has received regulatory approval for patients who have primarily soft-tissue metastases. Future r There are still unmet needs that may be met by therapeutic vaccines. r Successful vaccines likely will be those that induce or enhance recognition of patient-specific autologous neoantigens that result from nonsynonymous mutations contained in autologous tumor cells.Signal transduction inhibitors and anticheckpoint antibodies have significantly improved survival for metastatic melanoma patients, but most still die within 5 years. Vaccine approaches to induce immunity to well-characterized melanoma-associated antigens, or to antigens expressed on allogeneic tumor cell lines, have not resulted in approved agents. Despite the limitations associated with the immunosuppressive tumor microenvironment, there now is one intralesional autologous vaccine approved for patients who have primarily soft-tissue metastases. There is continued interest in patient-specific vaccines, especially dendritic cell vaccines that utilize ex vivo loading of autologous antigen, thus bypassing certain in vivo immunosuppressive cells and cytokines. Because of their mechanism of action and limited toxicity, they are potentially synergistic or additive to other antimelanoma therapies. A recent commentary concluded that there is a potential role for therapeutic vaccines in cancer therapy despite the clinical success of immune checkpoint inhibitors [1]. A similar conclusion previously was made for metastatic melanoma, in which it was argued that there is a strong rationale for therapeutic anticancer vaccines against metastatic melanoma even though to date no antimelanoma vaccines had been proven to be effective, and the best chance for success rested on approaches leading to recognition of autologous tumor cell antigens (tumor-associated antigen [TAA]) [2]. Furthermore, the suggestion that therapeutic vaccine research was no longer relevant because of the success of new targeted therapies including BRAF/MEK and immune-checkpoint inhibitors was refuted. The following is an update regarding these issues.

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“…However, the long-term survival results associated with this approach are quite encouraging in melanoma [12,13]. Recent improvements in manufacturing have made it possible to proceed with a randomized Phase III trial designed for the regulatory approval of such a product.…”

Section: Erroneous Assumption 1: All Melanoma Vaccines Have Proven Tomentioning

confidence: 99%

Is Vaccine Research still Relevant for Metastatic Melanoma?

Dillman¹

2014

Melanoma Manag.

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Phase II Trial of Dendritic Cells Loaded with Antigens from Self-Renewing, Proliferating Autologous Tumor Cells as Patient-Specific Antitumor Vaccines in Patients with Metastatic Melanoma: Final Report

Abstract: NCI-V01-1646).

Cited by 67 publications

References 27 publications

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

An Update on the Relevance of Vaccine Research for the Treatment of Metastatic Melanoma

Is Vaccine Research still Relevant for Metastatic Melanoma?

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