PMID- 31589347
OWN - NLM
STAT- MEDLINE
DCOM- 20191209
LR  - 20200108
IS  - 1365-3083 (Electronic)
IS  - 0300-9475 (Linking)
VI  - 90
IP  - 6
DP  - 2019 Dec
TI  - Exploiting autoimmunity unleashed by low-dose immune checkpoint blockade to treat 
      advanced cancer.
PG  - e12821
LID - 10.1111/sji.12821 [doi]
AB  - As a result of the cancer immunotherapy revolution, more than 2000 
      immuno-oncology agents are currently being tested or are in use to improve 
      responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was 
      awarded to James P. Allison and Tasuku Honjo for their development of cancer 
      therapy by the blockade of co-inhibitory signals. Unfortunately, manipulation of 
      the co-inhibitory receptors has also resulted in a safety issue: widespread 
      iatrogenic immune-related adverse events (irAEs). Autoimmunity is emerging as the 
      nemesis of immunotherapy. Originally, it was assumed that CTLA-4 blockade 
      selectively targets T cells relevant to the antitumour immune response. However, 
      an uncontrolled pan T cell activation was induced compromising tolerance to 
      healthy self-tissues. The irAEs are very similar to that of a chronic 
      graft-versus-host-disease (GVHD) reaction following allogeneic bone marrow 
      transplantation (BMT). We hypothesized that ipilimumab induced a 
      graft-versus-malignancy (GVM) effect, which eradicated metastatic melanoma in a 
      minority of patients, but also involved an auto-GVHD reaction that resulted in 
      widespread autoimmunity in the majority. Therefore, we argued for a profound 
      theoretical point against the consensus of experts. The task is not to 
      desperately put the genie back in the bottle by immune-suppressive treatments, 
      but instead to harness the autoimmune forces. In this way, the same goal could be 
      achieved by an antibody as by the adoptive transfer of alloreactive donor 
      lymphocytes, but without severe GVHD. The proof-of-principle of a 
      low-dose-combination immune checkpoint therapy, consisting only of approved drugs 
      and treatments, was demonstrated in 111 stage IV cancer patients.
CI  - (c) 2019 The Scandinavian Foundation for Immunology.
FAU - Bakacs, Tibor
AU  - Bakacs T
AUID- ORCID: 0000-0002-9145-9276
AD  - PRET Therapeutics Ltd., Budapest, Hungary.
FAU - Moss, Ralph W
AU  - Moss RW
AD  - Moss Reports, Blue Hill, Maine.
FAU - Kleef, Ralf
AU  - Kleef R
AD  - Immunology & Integrative Oncology, Kleef Hyperthermie, Vienna, Austria.
FAU - Szasz, Marcell A
AU  - Szasz MA
AD  - Cancer Centre, Semmelweis University, Budapest, Hungary.
FAU - Anderson, Colin C
AU  - Anderson CC
AD  - Departments of Surgery and Medical Microbiology & Immunology, Alberta Diabetes 
      Institute, Alberta Transplant Institute, University of Alberta, Edmonton, 
      Alberta, Canada.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20191007
PL  - England
TA  - Scand J Immunol
JT  - Scandinavian journal of immunology
JID - 0323767
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (CTLA4 protein, human)
SB  - IM
MH  - Antineoplastic Agents, Immunological/administration & dosage/adverse 
      effects/*therapeutic use
MH  - Autoimmunity/*drug effects
MH  - Biomarkers, Tumor/*antagonists & inhibitors
MH  - CTLA-4 Antigen/antagonists & inhibitors/genetics/metabolism
MH  - Humans
MH  - Lymphocyte Activation/drug effects/immunology
MH  - *Molecular Targeted Therapy
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - Neoplasms/*drug therapy/genetics/*immunology/pathology
MH  - Off-Label Use
MH  - Proof of Concept Study
MH  - Signal Transduction/drug effects
MH  - T-Lymphocytes/drug effects/immunology/metabolism
MH  - Treatment Outcome
OTO - NOTNLM
OT  - hyperthermia
OT  - immune checkpoint inhibitors
OT  - immune-related adverse events
OT  - interleukin-2
OT  - ipilimumab
OT  - low-dose-combination therapy
OT  - nivolumab
OT  - tolerance
EDAT- 2019/10/08 06:00
MHDA- 2019/12/18 06:00
CRDT- 2019/10/08 06:00
PHST- 2019/07/03 00:00 [received]
PHST- 2019/07/31 00:00 [revised]
PHST- 2019/08/26 00:00 [accepted]
PHST- 2019/10/08 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2019/10/08 06:00 [entrez]
AID - 10.1111/sji.12821 [doi]
PST - ppublish
SO  - Scand J Immunol. 2019 Dec;90(6):e12821. doi: 10.1111/sji.12821. Epub 2019 Oct 7.