- Jul 2018
-
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
-
On 2017 Mar 25, Gerhard Holt commented:
Eliminating S.A.S.P. cells : Targeting Senescence Specific Surface Antigens
with CAR-T cells, mAbs or Minicells ?
by Gerhard HoltResearch into cellular aging and the Senescence-Associated Secretory Phenotype indicates that selective elimination of senescent cells may provide substantial benefits - potentially including increases in healthspan.[1]
Many surface antigens may be differentially expressed on senescent/SASP cells relative to non-senescent cells. Ideally, the chosen cell surface antigen(s) would be highly specific to senescent/SASP cells to reduce collateral damage to non-senescent cells. For example, EFNB1 and/or EFNB3 may be appealing targets.[1]
These "Senescence Specific Surface Antigen" targets might - if necessary - include potentially spurious surface antigens that may have negligible causal relation to SASP but are nevertheless fairly specific. One could presumably also target multiple "SSSA"s to achieve better coverage.
Several methods to target cells expressing these SSSA's might be used - including :
(1) CAR-T cells vs the antigen(s). [2]
Pros :
Extensive removal of target cells. Long lasting surveillance against subsequent reemergence of the senescent/SASP cells with those surface antigens.
Cons :
May cause collateral damage or impair other important functions (for example - potentially - wound healing).
Questions :
Could one potentially embed a switchable "suicide gene" in the CAR-T cells, or perhaps a reversible switch to transiently deactivate the CAR-Ts either systemically or locally?
Could one also embed a highly specific artificial set of inducible surface antigens on the CAR-Ts to facilitate subsequent removal or modification by mAbs or minicells (see below)?[3]
(In the longer term one might also potentially examine logic-gated CAR-T cell approaches for increased specificity, or to target the absence of a surface antigen that is differentially expressed on Non-senescent cells ? [3])
(2) mAbs vs the antigen(s).
Pro :
Well established approach.
Con :
No longer term surveillance.
(3) Minicells vs the antigen(s). [4]
Pros :
Highly specific targeting. Minicells could also be targeted to multiple different SSSA's.
Can specifically carry cytotoxic medications to the target cells.
Can add siRNAs to the minicells to perform more subtle intracellular actions (perhaps inducing apoptosis, reversing (or accelerating) aberrant intracellular processes, attracting CAR-T cells, or modifying natural immune responses to the cell, or expressing alternative surface antigens).
Could be used in addition to CAR-T approaches, or perhaps as a backup to help selectively deactivate CAR-T cells if responses cause excessive collateral damage or if one needs to (perhaps temporarily) damp the response.
Con :
No long term surveillance.
Conclusion :
Targeting senescence specific surface antigens may be a useful way to selectively destroy senescent/SASP cells.
The application of CAR-T cell, mAb, and minicell approaches might be effective in this task, and will hopefully be the subject of further research.
REFERENCES :
[1] Zhu, Y. Tchkonia, T. et al. (2015) The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22.
www.ncbi.nlm.nih.gov/pubmed/25754370
[2] Kochenderfer JN et al. (2010) Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010 Nov 11;116(19):3875-86. doi: 10.1182/blood-2010-01-265041. Epub 2010 Jul 14.
www.bloodjournal.org/content/bloodjournal/116/19/3875.full.pdf
[3] Roybal, K.T., et al. (2016). Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779. dx.doi.org/10.1016/j.cell.2016.01.011
www.sciencedirect.com/science/article/pii/S0092867416000519
[4] MacDiarmid, J.A. et al. (2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat. Biotechnol. 27, 643–651.
www.nature.com/nbt/journal/v27/n7/pdf/nbt.1547.pdf
This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY.
-
- Feb 2018
-
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
-
On 2017 Mar 25, Gerhard Holt commented:
Eliminating S.A.S.P. cells : Targeting Senescence Specific Surface Antigens
with CAR-T cells, mAbs or Minicells ?
by Gerhard HoltResearch into cellular aging and the Senescence-Associated Secretory Phenotype indicates that selective elimination of senescent cells may provide substantial benefits - potentially including increases in healthspan.[1]
Many surface antigens may be differentially expressed on senescent/SASP cells relative to non-senescent cells. Ideally, the chosen cell surface antigen(s) would be highly specific to senescent/SASP cells to reduce collateral damage to non-senescent cells. For example, EFNB1 and/or EFNB3 may be appealing targets.[1]
These "Senescence Specific Surface Antigen" targets might - if necessary - include potentially spurious surface antigens that may have negligible causal relation to SASP but are nevertheless fairly specific. One could presumably also target multiple "SSSA"s to achieve better coverage.
Several methods to target cells expressing these SSSA's might be used - including :
(1) CAR-T cells vs the antigen(s). [2]
Pros :
Extensive removal of target cells. Long lasting surveillance against subsequent reemergence of the senescent/SASP cells with those surface antigens.
Cons :
May cause collateral damage or impair other important functions (for example - potentially - wound healing).
Questions :
Could one potentially embed a switchable "suicide gene" in the CAR-T cells, or perhaps a reversible switch to transiently deactivate the CAR-Ts either systemically or locally?
Could one also embed a highly specific artificial set of inducible surface antigens on the CAR-Ts to facilitate subsequent removal or modification by mAbs or minicells (see below)?[3]
(In the longer term one might also potentially examine logic-gated CAR-T cell approaches for increased specificity, or to target the absence of a surface antigen that is differentially expressed on Non-senescent cells ? [3])
(2) mAbs vs the antigen(s).
Pro :
Well established approach.
Con :
No longer term surveillance.
(3) Minicells vs the antigen(s). [4]
Pros :
Highly specific targeting. Minicells could also be targeted to multiple different SSSA's.
Can specifically carry cytotoxic medications to the target cells.
Can add siRNAs to the minicells to perform more subtle intracellular actions (perhaps inducing apoptosis, reversing (or accelerating) aberrant intracellular processes, attracting CAR-T cells, or modifying natural immune responses to the cell, or expressing alternative surface antigens).
Could be used in addition to CAR-T approaches, or perhaps as a backup to help selectively deactivate CAR-T cells if responses cause excessive collateral damage or if one needs to (perhaps temporarily) damp the response.
Con :
No long term surveillance.
Conclusion :
Targeting senescence specific surface antigens may be a useful way to selectively destroy senescent/SASP cells.
The application of CAR-T cell, mAb, and minicell approaches might be effective in this task, and will hopefully be the subject of further research.
REFERENCES :
[1] Zhu, Y. Tchkonia, T. et al. (2015) The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22.
www.ncbi.nlm.nih.gov/pubmed/25754370
[2] Kochenderfer JN et al. (2010) Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010 Nov 11;116(19):3875-86. doi: 10.1182/blood-2010-01-265041. Epub 2010 Jul 14.
www.bloodjournal.org/content/bloodjournal/116/19/3875.full.pdf
[3] Roybal, K.T., et al. (2016). Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779. dx.doi.org/10.1016/j.cell.2016.01.011
www.sciencedirect.com/science/article/pii/S0092867416000519
[4] MacDiarmid, J.A. et al. (2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat. Biotechnol. 27, 643–651.
www.nature.com/nbt/journal/v27/n7/pdf/nbt.1547.pdf
This comment, imported by Hypothesis from PubMed Commons, is licensed under CC BY.
-