Single-Step Antigen Loading and Activation of Dendritic Cells by mRNA Electroporation for the Purpose of Therapeutic Vaccination in Melanoma Patients

8537 Background: Therapeutic vaccination with autologous dendritic cells (DC) and Interferon alfa-2b (IFNa) both have low activity in patients with advanced melanoma. Combination therapy might be advantageous because of their complementary mechanism of action. Methods: We are investigating the safety and activity of an autologous DC-based melanoma vaccine in patients with advanced melanoma in a single institution phase IB clinical trial. Following leucapheresis and enrichment in a semi-closed culture system, adherent PBMC are cultured in IL-4 and GM-CSF supplemented medium for 6 days and cryo-preserved. Upon thawing, 15.106 DC are electroporated with synthetic mRNA that encodes a fusion protein between LAMP and one of 6 melanoma associated antigens (MAGE.A-1, MAGE.A-3, MAGE.C2, MELANA/MART1, Tyrosinase and gp100). DC vaccines are administered by 6 bi-weekly ID/SC injections and every 6–8w thereafter. Results: 15 pts (10M/5F; median age 52, range 27–72) with stage IIIC-IV melanoma have been recruited. Ten pts were able to receive ≥ 6 vaccinations. Toxicity was limited to grade 1 or 2 local skin reactions at the vaccine administration sites in all pts. Two pts had a regression of subcutaneous (sc) metastases during DC vaccination and one of these pts remains disease-free after 18 mths of follow-up (following the resection of a single residual metastasis). An additional pt remains disease-free following surgery of in transit metastases at 8 months of follow-up. Three out of four pts who were treated with IFNa-2b (5 106 U 3x/week sc) at progression developed skin depigmentation (leucoderma punctata) and in 2 of these pts an objective tumor response was documented (PR and CR, including complete regression of skin, lymph, liver and skeletal metastases). Both responses are ongoing at 9 and 11 months of follow-up. Conclusions: These preliminary observations indicate a potential for IFNa-2b to mediate auto-immune breakthrough and tumor regression in advanced melanoma patients vacinated with a mRNA electroporated DC-vaccine. Further investigation of this combination immunotherapy in advanced melanoma patients is ongoing. No significant financial relationships to disclose.

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A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Cancer Immunology Immunotherapy ◽

10.1007/s00262-017-2085-9 ◽

2017 ◽

Vol 67 (2) ◽

pp. 285-298 ◽

Cited By ~ 22

Author(s):

Olivier Gasser ◽

Katrina J. Sharples ◽

Catherine Barrow ◽

Geoffrey M. Williams ◽

Evelyn Bauer ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

High Risk ◽

Phase I ◽

High Risk Melanoma ◽

Risk Melanoma ◽

Melanoma Patients ◽

Polyfunctional T Cells

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Dendritic Cells: Their Role in the Immune Response to Infectious Organisms and Their Potential Use in Therapeutic Vaccination

Immunotherapy for Infectious Diseases ◽

10.1385/1-59259-171-x:99 ◽

2003 ◽

pp. 99-116

Author(s):

Smriti K. Kundu-Raychaudhuri ◽

Edgar G. Engleman

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Therapeutic Vaccination ◽

Potential Use

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Ribonucleic Acid Engineering of Dendritic Cells for Therapeutic Vaccination: Ready ‘N Able to Improve Clinical Outcome?

Cancers ◽

10.3390/cancers12020299 ◽

2020 ◽

Vol 12 (2) ◽

pp. 299

Author(s):

Yannick Willemen ◽

Maarten Versteven ◽

Marc Peeters ◽

Zwi N. Berneman ◽

Evelien L. J. Smits

Keyword(s):

Dendritic Cells ◽

Immune System ◽

Ribonucleic Acid ◽

Central Place ◽

Future Research ◽

Therapeutic Vaccination ◽

Effective Form ◽

Significant Toxicity ◽

Clinical Responses ◽

Reliable Quantification

Targeting and exploiting the immune system has become a valid alternative to conventional options for treating cancer and infectious disease. Dendritic cells (DCs) take a central place given their role as key orchestrators of immunity. Therapeutic vaccination with autologous DCs aims to stimulate the patient’s own immune system to specifically target his/her disease and has proven to be an effective form of immunotherapy with very little toxicity. A great amount of research in this field has concentrated on engineering these DCs through ribonucleic acid (RNA) to improve vaccine efficacy and thereby the historically low response rates. We reviewed in depth the 52 clinical trials that have been published on RNA-engineered DC vaccination, spanning from 2001 to date and reporting on 696 different vaccinated patients. While ambiguity prevents reliable quantification of effects, these trials do provide evidence that RNA-modified DC vaccination can induce objective clinical responses and survival benefit in cancer patients through stimulation of anti-cancer immunity, without significant toxicity. Succinct background knowledge of RNA engineering strategies and concise conclusions from available clinical and recent preclinical evidence will help guide future research in the larger domain of DC immunotherapy.

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Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update

Pharmaceutics ◽

10.3390/pharmaceutics12020092 ◽

2020 ◽

Vol 12 (2) ◽

pp. 92 ◽

Cited By ~ 8

Author(s):

Jan Dörrie ◽

Niels Schaft ◽

Gerold Schuler ◽

Beatrice Schuler-Thurner

Keyword(s):

Dendritic Cells ◽

Tumor Antigens ◽

Ex Vivo ◽

Active Immunotherapy ◽

Pancreatic Cancers ◽

Short And Long Term ◽

Melanoma Patients ◽

And Function ◽

Tumor Mrna

Over the last two decades, dendritic cell (DC) vaccination has been studied extensively as active immunotherapy in cancer treatment and has been proven safe in all clinical trials both with respect to short and long-term side effects. For antigen-loading of dendritic cells (DCs) one method is to introduce mRNA coding for the desired antigens. To target the whole antigenic repertoire of a tumor, even the total tumor mRNA of a macrodissected biopsy sample can be used. To date, reports have been published on a total of 781 patients suffering from different tumor entities and HIV-infection, who have been treated with DCs loaded with mRNA. The majority of those were melanoma patients, followed by HIV-infected patients, but leukemias, brain tumors, prostate cancer, renal cell carcinomas, pancreatic cancers and several others have also been treated. Next to antigen-loading, mRNA-electroporation allows a purposeful manipulation of the DCs’ phenotype and function to enhance their immunogenicity. In this review, we intend to give a comprehensive summary of what has been published regarding clinical testing of ex vivo generated mRNA-transfected DCs, with respect to safety and risk/benefit evaluations, choice of tumor antigens and RNA-source, and the design of better DCs for vaccination by transfection of mRNA-encoded functional proteins.

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