Download - immunoregulation
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Genetically Engineered T Cells
Selecting for high affinity receptors
Extreme toxicitiesNormal T cell receptor/antigen/MCH complexes are relatively low affinity
On-target, off tumor
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Addressing the Issue of Acute Toxicity of Genetically Engineered T cells
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N
CN
C
C
C
N
N
C
O
H2N
H
CH2
O
CH2
CH2HO
ATP ADP
HSV thymidine kinase
N
CN
C
C
C
N
N
C
O
H2N
H
CH2
O
CH2
CH2OP
O
O-
O-
ACV-TPcellular kinases
• acyclovir, first specific antiviral drug• used to treat herpes simplex I and II and varicella zoster virus infections
Antiviral Drugs
promiscuous, broad substrate specificity
active drugcellular TK does not phosphorylate ACV
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PPP-
O-C
H2
O
GC4
PPi
HSV DNA polymerase
* * * *
3′
C4*
P
-O-C
H2
O
Gchain
termination
Acyclovir: Mechanism of ActionACV binds with a 30-fold higher affinity to HSV DNA polymerase relative to cellular polymerase
OHOH
• ACV selectively phosphorylated by HSV TK• ACV-TP binds selectively to HSV DNA pol• ACV functions as a chain terminator
3′ - 5′ phosphodiester bonds
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Addressing the Issue of Acute Toxicity of Genetically Engineered T cells
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Autologous Adoptive Cell Therapy
Immunosuppressive environment
Even after reinfusion of expanded and activated T
cells the immunosuppressive environment of tumors and
natural T cell regulatory mechanisms limit their
effectiveness, particularly in solid tumors
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What if Rather than Go through all the Bioengineering Involved in this Thought Experiment We Instead Reactivated the Natural
Diverse T Cells Already Present in the Tumor in the Body?
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An Alternative Approach to T Cell Therapy: Immuno-Regulation
• Soon after T cells are activated a regulatory mechanism kicks in that begins to turn them off
CTLA-4 is a member of the CD28 family of co-receptors except it inhibits rather than activates T cells
CTLA = cytotoxic lymphocyte antigen
Upregulated 48 to 72
hours after activation
Prevents pathogenic
autoimmune disorders
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T Regulatory Cells Also Use CTLA-4 in Regulating T Cell Activation
• Increased CTLA-4• Increased CD25• No production of IL-2
Tregs
CTLA-4
B7, CD80
Tregs
antigen presenting
cell
• Interaction results in internalization and degradation of CD80 on antigen presenting cells
• APCs can no longer provide signal 2 for T cell activation
Ag
MHC
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T Regulatory Cells Also Serve as a Sponge for IL-2
Tregs• Tregs do not express
IL-2 but produce large amounts of CD25, a high affinity IL-2 receptor
IL-2
IL-2IL-2
IL-2
• Binding of IL-2 to Tregs stimulates Treg proliferation and deprives other T cell types of IL-2
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Lympho-Depletion Prior to Adoptive T Cell Therapy
Lympho-depletion may work in part by reducing the number of immunosuppressive lymphocytes
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Trials Using Ipilimumab, an antibody to CTLA-4, for Metastatic Melanoma
Gp100 vaccine
Ipi alone
Ipi + gp100 vaccine
It’s not much, but it is a start
676 patients comparing Ipilimumab with and without vaccination with GP100
GP100, a major TAA in melanoma
Hodi et al NEJM 2010
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Combining Standard Chemotherapy With and Without Ipilimumab
Bondarenko et al NEJM 2011
• Immunotherapies often work better with combined with cytotoxic chemotherapies
• Standard of care chemotherapy for melanoma is dacarbazine
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Combining Ipilimumab with Standard Chemotherapy: Overall Survival
Effect of Ipilimumab on overall survival disappointing
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Dacarbazine is an Imadazotetrazine Prodrug
Imadazotetrazines are alkylating agents
temozolomide
dacarbazine
Methyldiazonium ions active alkylating agents
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Alkylating Agent Efficacy can be Influenced by DNA Repair Capacity
alkylating agents
N
CN
C
C
C
N
N
C1
23
4
56
7
8
9
O
H2N
CH3O6-methyl G can base pair with C or T alkylation at N7 can
lead to depurination
promotes cleavage of N-glycosidic bond
10,000 depurination events per day even in the absence of alkylating agents
MGMT – methylguanine methyl transferase
Temozolomide – alkylating agent used to treat glioblastoma
overexpression of MGMT leads to temozolomide resistance
accepts methyl group from base inactivating enzyme
gaps can be repaired but if damage too great, the guardian of the genome, p53, can induce cell death
DNA repair -
good
DNA repair -
bad
Dacarbazine (or temozolomide)
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There’s More to the Tumor Immunosuppressive Environment than the Down-Regulation of T Cells by
CTLA-4
• PD-1 is also a negative regulator of T cell activation
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The SHP Proteins are Tyrosine Phosphatases
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Activation of SHP Phosphatases Disrupt Numerous Signaling Pathways
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Nivolumab Trials for Advanced Melanoma
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Combining Anti-CTLA-4 and Anti-PD-1 Therapies for Melanoma
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Outcomes of the Trial
BRAF a tyrosine kinase involved in melanoma, which can be targeted by a TKI
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Adverse Events With New Immuno-modulatory Agents
Immune related adverse events
Systems affected
• Skin – 3-4 weeks
• GI tract/liver – 6-7 weeks
• endocrine – 9 weeks
Patients who develop anti-CTLA-4 associated endocrinopathies may present with nonspecific symptoms such as:
• fatigue• headache • nausea • behavioral changes, visual impairments,
memory loss, decreased libido, • anorexia, • insomnia, • cold or heat intolerance.
hypothalamic-pituitary-thyroidal axis