ISCT Speaker Declaration • The presented clinical data and findings are the result of experimental trial(s) and/or in accordance with Article 37 in the 2013 Helsinki Declaration amendment. In both cases the procedures were performed with the approval of all required regulatory authorities and with signed informed consent of all patients following principles as described in the current World Medical Association Declaration of Helsinki.
39
Embed
ISCT Speaker Declaration - cdn.ymaws.com · scFv . Recognition of intact molecule, including non-proteins CAR T Cells Recognition of peptides processed through MHC Transgenic TCR
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
ISCT Speaker Declaration
• The presented clinical data and findings are the
result of experimental trial(s) and/or in accordance
with Article 37 in the 2013 Helsinki Declaration
amendment. In both cases the procedures were
performed with the approval of all required regulatory
authorities and with signed informed consent of all
patients following principles as described in the
current World Medical Association Declaration of
Helsinki.
CAR-T Cells for
Hematological Malignancies
Carlos A. Ramos, MD, et al.
ISCT North America Meeting 2016
Disclosure
• The Center for Cell and Gene Therapy at BCM had a
Research Collaboration with Celgene Corporation and
Bluebird Bio when some of this work was done
• Many investigators at the Center (including the presenter)
have patent applications in the fields of T-cell and gene-
modified T-cell therapy for cancer
T cells versus antibodies
• Highly targeted
• Can actively traffic to tumor sites
• Expand in vivo
• Persist long term
• Gene transfer allows:
– Improved antigen recognition
– Countermeasures to tumor immune evasion
– Introduction of safety mechanisms
Earliest examples of T-cell therapy
for hematological malignancies
• Allogeneic BMT GVL (co-infused T cells) – Initially unappreciated
• DLI* – For relapse
(Sullivan et al., NEJM 1989; Kolb et al., Blood 1990)
– PTLD** (Papadopoulos et al., NEJM 1994)
• Tumor (virus) specific T cells (EBV-CTLs) – PTLD
(Rooney et al., Lancet 1995)
**Donor Lymphocyte Infusion
**Post Transplant Lymphoproliferative Disorder
High risk of severe GVHD
neo
EBV
Donor Recipient
T cells present in graft
T cells given as DLI after BMT
EBV-specific cytotoxic T lymphocytes
EBV-Cytotoxic T Lymphocytes
(CTL) work in other malignancies
• Hodgkin lymphoma (Bollard et al., J Exp Med 2004)
• DLBCL (Bollard et al., Blood 2007)
• NPC (Straathof et al., Blood 2005)
• Optimization has included:
– Overexpression of weakly
immunogenic proteins
– Introduction of resistance
to the effects of TGF-β
LMP 1
LMP 2
Type 2 Latency
Hodgkin’s disease/NHL
Nasopharyngeal carcinoma
EBNA-1
Making T-cell therapy more broadly
applicable…
• Most tumors do not contain exogenous, viral antigens
• Can we consistently manufacture T cells that recognize
weak, tumor associated antigens?
– One approach: genetically engineer T cells to introduce new T-
cell receptors
• αβ (native T-cell receptors)
• Chimeric Antigen Receptors (CAR)
T Cell T cell
Chimeric Antigen Receptors
CAR
(Ramos & Dotti, Expert Opin Biol Ther 2011)
Gross, Waks & Eshhar, PNAS 1989
vL
Monoclonal
Antibody
α β
TCR complex
γ ε ε δ
ζ ζ Tumor
Tumor Antigen
Intracytoplasmic
vH
scFv
Recognition of
intact molecule,
including non-proteins
CAR T Cells
Recognition of
peptides processed
through MHC
Transgenic TCR T cells
Chimeric vs. transgenic
native T-Cell Receptors
CD19 + + –/+
CD20 – + –/+
CD38 + + +++
CD138 – – +++
sIg (κ/λ) – + (IgM,IgD) –/+
Selecting B-cell lymphoma antigens
B lymphocyte
precursor
Naïve mature B
lymphocyte
Plasma cell
Antigen-independent Antigen-dependent
HSC
Clinical trials using 1st generation
CD19.CAR-T cells
• Feasibility of the approach was established
• Lack of significant anti-tumor effects
• Limited persistence of CAR-modified T cells
T cell T cell ζ
T cell
ζ
Incomplete activation of first generation
CAR-T cells
Killing of tumor
cells
Incomplete
activation of
T cells
CD28
2nd gen
CAR
B7
1st gen
CAR
CD28
Improved T cell
activation and
proliferation Tumor Tumor
First vs. later generation CARs
Spacer Linker
scFv
ζ (zeta)
ζ
CD28
Ectodomain
Transmembrane
Endodomain 4-1BB
CD28
ζ
First Second Third generation
Are 2nd gen CAR-T cells superior
to 1st gen CAR T cells?
(CRETI study)
CAR.CD19-28
retrovirus
PBMC activation
Infusion
Peripheral blood
draw or apheresis
CAR.CD19-CD28 T cells CAR.CD19 T cells
Expansion in IL-2
CAR.CD19
retrovirus Transduction
QA/QC testing
and freezing
QA/QC testing
and freezing No lymphodepletion!
Patient details Age Diagnosis Previous therapy Disease status