PMID- 36045304 OWN - NLM STAT- MEDLINE DCOM- 20230224 LR - 20231213 IS - 1432-0851 (Electronic) IS - 0340-7004 (Print) IS - 0340-7004 (Linking) VI - 72 IP - 3 DP - 2023 Mar TI - Divergent clinical outcomes in a phase 2B trial of the TLPLDC vaccine in preventing melanoma recurrence and the impact of dendritic cell collection methodology: a randomized clinical trial. PG - 697-705 LID - 10.1007/s00262-022-03272-8 [doi] AB - BACKGROUND: A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods. METHODS: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups. RESULTS: 144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity. CONCLUSIONS: Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy. CI - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Adams, Alexandra M AU - Adams AM AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Carpenter, Elizabeth L AU - Carpenter EL AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. elcarp@mac.com. FAU - Clifton, Guy T AU - Clifton GT AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Vreeland, Timothy J AU - Vreeland TJ AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Chick, Robert C AU - Chick RC AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - O'Shea, Anne E AU - O'Shea AE AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - McCarthy, Patrick M AU - McCarthy PM AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Kemp Bohan, Phillip M AU - Kemp Bohan PM AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Hickerson, Annelies T AU - Hickerson AT AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Valdera, Franklin A AU - Valdera FA AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Tiwari, Ankur AU - Tiwari A AD - Department of Surgery, University of Texas Health Sciences Center, San Antonio, Texas, USA. FAU - Hale, Diane F AU - Hale DF AD - Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA. FAU - Hyngstrom, John R AU - Hyngstrom JR AD - Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. FAU - Berger, Adam C AU - Berger AC AD - Department of Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. FAU - Jakub, James W AU - Jakub JW AD - Department of Surgery, Mayo Clinic, Jacksonville, FL, USA. FAU - Sussman, Jeffrey J AU - Sussman JJ AD - Department of Surgery, University of Cincinnati, Cincinnati, OH, USA. FAU - Shaheen, Montaser F AU - Shaheen MF AD - Department of Medicine, University of Arizona, Tucson, AZ, USA. FAU - Yu, Xianzhong AU - Yu X AD - Department of Biological Sciences, Clemson University, Clemson, SC, USA. FAU - Wagner, Thomas E AU - Wagner TE AD - Orbis Health Solutions, Greenville, SC, USA. FAU - Faries, Mark B AU - Faries MB AD - Department of Surgery, The Angeles Clinic, Santa Monica, CA, USA. FAU - Peoples, George E AU - Peoples GE AD - Cancer Vaccine Development Program, San Antonio, TX, USA. LA - eng PT - Journal Article PT - Randomized Controlled Trial DEP - 20220901 PL - Germany TA - Cancer Immunol Immunother JT - Cancer immunology, immunotherapy : CII JID - 8605732 RN - 0 (Cancer Vaccines) RN - 143011-72-7 (Granulocyte Colony-Stimulating Factor) SB - IM MH - Humans MH - *Melanoma MH - *Cancer Vaccines MH - Dendritic Cells MH - Granulocyte Colony-Stimulating Factor MH - Melanoma, Cutaneous Malignant PMC - PMC9433518 OTO - NOTNLM OT - Cancer vaccine OT - Dendritic cell OT - Immunotherapy OT - Melanoma OT - Personalized medicine COIS- The protocol was approved by the Western Institutional Review Board and all patients provided informed consent for participation. Dr. Faries is an advisor for Bristol-Myers Squibb, Sanofi, Array Bioscience and Pulse Bioscience. Dr. Wagner is an employee of Orbis Health Solutions. Dr. Peoples is employed by Orbis Health Solutions and Cancer Insight; is a consultant for Rapamycin Holdings, Heat Biologics, Abexxa Biologics, and Pelican Therapeutics; and has received funding from the above as well as Sellas Life Sciences and Genentech. Dr Jakub served on a Novartis Melanoma Surgical Oncology Advisory Board. Dr. Clifton is employed by Parthenon Therapeutics. The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the US Army Medical Department, the Department of the Army, Department of the Air Force, Department of Defense, or the US Government. The voluntary, fully informed consent of the subjects used in this research was obtained as required by 32 CFR 219 and DODI 3216.02_AFI40-402. EDAT- 2022/09/01 06:00 MHDA- 2023/02/25 06:00 PMCR- 2022/09/01 CRDT- 2022/08/31 23:28 PHST- 2022/03/07 00:00 [received] PHST- 2022/08/01 00:00 [accepted] PHST- 2022/09/01 06:00 [pubmed] PHST- 2023/02/25 06:00 [medline] PHST- 2022/08/31 23:28 [entrez] PHST- 2022/09/01 00:00 [pmc-release] AID - 10.1007/s00262-022-03272-8 [pii] AID - 3272 [pii] AID - 10.1007/s00262-022-03272-8 [doi] PST - ppublish SO - Cancer Immunol Immunother. 2023 Mar;72(3):697-705. doi: 10.1007/s00262-022-03272-8. Epub 2022 Sep 1.