Messenger RNA vaccination and B-cell responses in NSCLC patients.
Abstract
2573^ Background: Vaccination with mRNA is a novel technology in cancer immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules (RNActive) coding for five non small cell lung cancer (NSCLC)-associated tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC. Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3 pts. were treated at three dose levels (400µg, 800µg and 1600µg CV9201) and observed for DLTs to select the highest tolerated dose for phase IIa. Primary endpoint was safety and tolerability; secondary endpoints were immune response, clinical efficacy and survival. Pts. received up to five vaccinations of CV9201 within 15 weeks. Antigen-specific immune responses against each of the 5 antigens were measured at baseline, and two weeks after the 3 rd and 5 th vaccination. Frequency of lymphocyte subsets and expression of activation and maturation markers were measured and retrospectively correlated with immunological and clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase IIa); No DLTs occurred, and the 1600 µg dose was investigated in phase IIa. The most frequent related adverse events were mild to moderate injection site reactions and flu-like symptoms. 3 patients (7%) had potentially related grade 3 AEs (fatigue, injection site granuloma, asthma attack) and no related SAEs were reported. There were no objective responses. Data on PFS and survival will be presented. Antigen specific immune responses against at least one antigen were induced in 65% of pts. (39% cellular and 49% humoral). Consistently, a significant ≥2 fold increase of pre germinal center B cells (pGCB) was observed in 61% of pts. This increase of pGCB correlated significantly (p=0.0028) with increase of total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase during treatment. Conclusions: Vaccination with CV9201 has a favorable safety profile and induces T and B cell responses against all included antigens. Vaccine-induced increase of pGCB is a new finding and might be used as a biomarker in cancer immunotherapy.
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mRNA vaccines have shown good efficacy in the treatment of acute myelocytic leukemia (AML), non-small cell lung cancer (NSCLC), and melanoma.
“mRNA vaccines have shown good efficacy in the treatment of acute myelocytic leukemia (AML),339–341 non-small cell lung cancer (NSCLC),342,343 and melanoma344–348 (Table 3).”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [342]
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Advances in COVID-19 mRNA vaccine development
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A novel, disruptive vaccination technology: Self-adjuvanted RNActive <sup>®</sup> vaccines
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“For the NSCLC cocktail CV9201, five tumor-associated antigens were chosen: MAGE-C1, MAGE-C2, NY-ESO-1, survivin, and 5T4.(32,33) In the prostate-carcinoma study with CV9103, an unexpectedly high level of cellular immunogenicity was observed.”
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Heine, A., Juranek, S., & Brossart, P. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01339-1 · Cited by 185 · see citing works
“≥ 2 fold increase of pre germinal center B cells; no objective clinical responses follow up trial terminated due to low recruitment NCT01915524 [163]”
BackgroundSebastian, M., Papachristofilou, A., Weiß, C., Früh, M., Cathomas, R. L., Hilbe, W., Wehler, T., Rippin, G., Koch, S. D., Scheel, B., et al. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-748 · Cited by 142 · see citing works
Self-citationKallen, K., & Theß, A. (2013) · Therapeutic Advances in Vaccines · doi:10.1177/2051013613508729 · Cited by 120 · see citing works
Self-citationThe ReNAissanCe of mRNA-based cancer therapy
Van Lint, S., Renmans, D., Broos, K., Dewitte, H., Lentacker, I., Heirman, C., Breckpot, K., & Thielemans, K. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.957685 · Cited by 95 · see citing works
Vallazza, B., Petri, S., Poleganov, M. A., Eberle, F., Kuhn, A. N., & Şahin, U. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1288 · Cited by 73 · see citing works
mRNA vaccines: Past, present, future
Karam, M., & Daoud, G. (2022) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2022.05.003 · Cited by 74 · see citing works
“[30] Sebastian M , von Boehmer L , Zippelius A , Mayer F , Reck M , Thomas DA , et al.”
BackgroundMethodRNA Therapeutics: How Far Have We Gone?
Coutinho, M. F., Matos, L., Santos, J. I., & Alves, S. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-19966-1_7 · Cited by 44 · see citing works
Hattinger, E., Scheiblhofer, S., Roesler, E., Thalhamer, T., Thalhamer, J., & Weiss, R. (2015) · Journal of Immunology Research · doi:10.1155/2015/797421 · Cited by 28 · see citing works
“2 Journal of Immunology Research mRNA encoding tumor-associated antigens [15, 16].”
BackgroundThe European Regulatory Environment of RNA-Based Vaccines
Hinz, T., Kallen, K., Britten, C. M., Flamion, B., Granzer, U., Hoos, A., Huber, C., Khleif, S. N., Kreiter, S., Rammensee, H., et al. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6481-9_13 · Cited by 30 · see citing works
Self-citationSebastian, M. (2014) · Forum · doi:10.1007/s12312-014-1087-1
Self-citationKallen, K. (2014) · Springer eBooks · doi:10.1007/978-3-319-05104-8_15
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- Authors
- Sebastian, M., von Boehmer, L., Zippelius, A., Mayer, F., Reck, M., Atanackovic, D., Thomas, M., Schneller, F., Stoehlmacher-Williams, J., Goekkurt, E., Bernhard, H., Groeschel, A., Scheel, B., Koch, S. D., Lander, T., Rippin, G., Wiegand, V., Gnad-Vogt, U. S., Kallen, K.-J., & Knuth, A.
- Affiliations
- Goethe University Frankfurt (DE)
- Department of Oncology, University Hospital Zurich, Zurich, Switzerland
- University Hospital of Basel (CH)
- University Hospital, Medical Center II, Tuebingen, Germany
- LungenClinic Grosshansdorf (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Heidelberg University (DE)
- TUM Klinikum (DE)
- University Hospital Carl Gustav Carus (DE)
- Universitätsklinikum Aachen (DE)
- Klinikum Darmstadt (DE)
- Internal Medicine V, Pneumology, University Hospital of the Saarland, Homburg/Saar, Germany
- CureVac (Germany) (DE)
- University Hospital Zurich (CH)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2012-05-20
- Volume
- 30
- Issue
- 15_suppl
- Pages
- 2573-2573
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2956482721
- Cited by
- 13
- References
- 0
- Citations by year
- 2022: 2 · 2021: 1 · 2019: 1 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 2
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- mRNA vaccination, cancer immunotherapy, non-small cell lung cancer, tumor-associated antigens, MAGE-C1, NY-ESO-1, survivin, 5T4, B cell response, CD4+ effector T cells, regulatory T cells, vaccine safety, dose escalation, humoral and cellular immune response
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