PMID- 37993874
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20231127
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 42
IP  - 1
DP  - 2023 Nov 22
TI  - CSPG4 CAR-redirected Cytokine Induced Killer lymphocytes (CIK) as effective 
      cellular immunotherapy for HLA class I defective melanoma.
PG  - 310
LID - 10.1186/s13046-023-02884-x [doi]
LID - 310
AB  - BACKGROUND: Even acknowledging the game-changing results achieved in the 
      treatment of metastatic melanoma with the use of immune checkpoint inhibitors 
      (ICI), a large proportion of patients (40-60%) still fail to respond or relapse 
      due to the development of resistance. Alterations in the expression of Human 
      Leukocyte Antigen class I (HLA-I) molecules are considered to play a major role 
      in clinical resistance to ICI. Cellular immunotherapy with HLA-independent 
      CAR-redirected lymphocytes is a promising alternative in this challenging setting 
      and dedicated translational models are needed. METHODS: In this study, we propose 
      an HLA-independent therapeutic strategy with Cytokine Induced Killer lymphocytes 
      (CIK) genetically engineered with a Chimeric Antigen Receptor (CAR) targeting the 
      tumor antigen CSPG4 as effector mechanism. We investigated the preclinical 
      antitumor activity of CSPG4-CAR.CIK in vitro and in a xenograft murine model 
      focusing on patient-derived melanoma cell lines (Mel) with defective expression 
      of HLA-I molecules. RESULTS: We successfully generated CSPG4-CAR.CIK from 
      patients with metastatic melanoma and reported their intense activity in vitro 
      against a panel of CSPG4-expressing patient-derived Mel. The melanoma killing 
      activity was intense, even at very low effector to target ratios, and not 
      influenced by the expression level (high, low, defective) of HLA-I molecules on 
      target cells. Furthermore, CAR.CIK conditioned medium was capable of upregulating 
      the expression of HLA-I molecules on melanoma cells. A comparable 
      immunomodulatory effect was replicated by treatment of Mel cells with exogenous 
      IFN-gamma and IFN-alpha. The antimelanoma activity of CSPG4-CAR.CIK was successfully 
      confirmed in vivo, obtaining a significant tumor growth inhibition of an 
      HLA-defective Mel xenograft in immunodeficient mice. CONCLUSIONS: In this study 
      we reported the intense preclinical activity of CSPG4-CAR.CIK against melanoma, 
      including those with low or defective HLA-I expression. Our findings support 
      CSPG4 as a valuable CAR target in melanoma and provide translational rationale 
      for clinical studies exploring CAR-CIK cellular immunotherapies within the 
      challenging setting of patients not responsive or relapsing to immune checkpoint 
      inhibitors.
CI  - (c) 2023. The Author(s).
FAU - Giraudo, Lidia
AU  - Giraudo L
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
FAU - Cattaneo, Giulia
AU  - Cattaneo G
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy. giulia.cattaneo@cshs.org.
AD  - Division of Surgical Oncology, Department of Surgery, Massachusetts General 
      Hospital, Harvard Medical School, Boston, MA, USA. giulia.cattaneo@cshs.org.
FAU - Gammaitoni, Loretta
AU  - Gammaitoni L
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
FAU - Iaia, Ilenia
AU  - Iaia I
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Donini, Chiara
AU  - Donini C
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Massa, Annamaria
AU  - Massa A
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Centomo, Maria Laura
AU  - Centomo ML
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Basirico, Marco
AU  - Basirico M
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
FAU - Vigna, Elisa
AU  - Vigna E
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Pisacane, Alberto
AU  - Pisacane A
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
FAU - Picciotto, Franco
AU  - Picciotto F
AD  - Dermatologic Surgery Section, Department of Surgery, Azienda Ospedaliera 
      Universitaria (AOU) Citta Della Salute E Della Scienza, Turin, TO, Italy.
FAU - Berrino, Enrico
AU  - Berrino E
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
AD  - Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, 
      Turin, TO, Italy.
FAU - Marchio, Caterina
AU  - Marchio C
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
AD  - Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, 
      Turin, TO, Italy.
FAU - Merlini, Alessandra
AU  - Merlini A
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Paruzzo, Luca
AU  - Paruzzo L
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Poletto, Stefano
AU  - Poletto S
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Caravelli, Daniela
AU  - Caravelli D
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
FAU - Biolato, Andrea Michela
AU  - Biolato AM
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
AD  - Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute 
      of Health, Luxembourg City, Luxembourg.
AD  - Faculty of Science, Technology and Medicine, University of Luxembourg, 
      Esch-Sur-Alzette, Luxembourg.
FAU - Bortolot, Valentina
AU  - Bortolot V
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Landoni, Elisa
AU  - Landoni E
AD  - Department of Microbiology and Immunology, University of North Carolina, Chapel 
      Hill, NC, USA.
FAU - Ventin, Marco
AU  - Ventin M
AD  - Division of Surgical Oncology, Department of Surgery, Massachusetts General 
      Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Ferrone, Cristina R
AU  - Ferrone CR
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
FAU - Aglietta, Massimo
AU  - Aglietta M
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Dotti, Gianpietro
AU  - Dotti G
AD  - Department of Microbiology and Immunology, University of North Carolina, Chapel 
      Hill, NC, USA.
FAU - Leuci, Valeria
AU  - Leuci V
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy.
FAU - Carnevale-Schianca, Fabrizio
AU  - Carnevale-Schianca F
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy.
FAU - Sangiolo, Dario
AU  - Sangiolo D
AD  - Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060, 
      Candiolo, TO, Italy. dario.sangiolo@unito.it.
AD  - Department of Oncology, University of Turin, Regione Gonzole 10, 10043, 
      Orbassano, TO, Italy. dario.sangiolo@unito.it.
LA  - eng
GR  - Ricerca Corrente 2023/Ministero della Salute/
GR  - Progetto CAR-T RCR-2019-23669115/Ministero della Salute/
GR  - IG-2017 20259/Associazione Italiana per la Ricerca sul Cancro/
GR  - Fondo Ricerca Locale 2022/Universita degli Studi di Torino/
PT  - Journal Article
DEP - 20231122
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (Cytokines)
RN  - 0 (Receptors, Chimeric Antigen)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (CSPG4 protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (Chondroitin Sulfate Proteoglycans)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - Cytokines
MH  - *Receptors, Chimeric Antigen/genetics
MH  - Immune Checkpoint Inhibitors
MH  - Immunotherapy, Adoptive/methods
MH  - Neoplasm Recurrence, Local
MH  - *Melanoma/genetics/therapy
MH  - Immunotherapy
MH  - Lymphocytes/pathology
MH  - Membrane Proteins
MH  - Chondroitin Sulfate Proteoglycans
PMC - PMC10664597
OTO - NOTNLM
OT  - CAR
OT  - CIK
OT  - CSPG4
OT  - HLA class-I
OT  - Immunotherapy
OT  - Melanoma
COIS- The authors declare that they have no competing interests.
EDAT- 2023/11/23 06:42
MHDA- 2023/11/27 12:43
PMCR- 2023/11/22
CRDT- 2023/11/23 00:03
PHST- 2023/08/16 00:00 [received]
PHST- 2023/11/02 00:00 [accepted]
PHST- 2023/11/27 12:43 [medline]
PHST- 2023/11/23 06:42 [pubmed]
PHST- 2023/11/23 00:03 [entrez]
PHST- 2023/11/22 00:00 [pmc-release]
AID - 10.1186/s13046-023-02884-x [pii]
AID - 2884 [pii]
AID - 10.1186/s13046-023-02884-x [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2023 Nov 22;42(1):310. doi: 10.1186/s13046-023-02884-x.