Immunotherapy for Cancer: Promises and Challenges

Immunotherapy for Cancer: Promises and Challenges

Loading
Loading Social Plug-ins...
Language: English
Save to myLibrary Download PDF
Go to Page # Page of 35

Description: Cancer is a genetic disease that results from sequential mutations. Why don’t vaccines work better to treat cancer? Immunity is a balance between action and restraint. Signaling pathways between T-cells and dendritic cells regulate T-cell activation status.

Activity of Anti–PD-1 Antibody in Patients with Treatment-Refractory Melanoma, Non–Small-Cell Lung Cancer, or Renal-Cell Cancer. Activity of Anti–PD-L1 Antibody in Patients with Advanced Melanoma and Non–Small-Cell Lung Cancer. Relationship between PD-L1 Expression and response rates in lung cancer.

 
Author: Edmund K. Waller MD PhD FACP (Senior) | Visits: 602 | Page Views: 925
Domain:  Medicine Category: Therapy 
Upload Date:
Link Back:
Short URL: https://www.wesrch.com/medical/pdfME1LYY000QCCL
Loading
Loading...



px *        px *

* Default width and height in pixels. Change it to your required dimensions.

 
Contents:
Immunotherapy for Cancer
Promises and Challenges
Edmund K. Waller, MD, PhD, FACP

Cancer is a genetic disease that
results from sequential mutations

Types of Tumor Antigens Recognized by T Cells

Cancer Immunotherapy has been
disappointing

Why don’t vaccines work better to treat cancer?
Immunity is a balance between action and restraint

Signaling pathways between T-cells and dendritic
cells regulate T-cell activation status

Topalian et al. 2011 J Clin Oncol 29:4828-4836

Programmed Death-1 (PD-1)
Function

Pardoll DM. Nat Rev Cancer 2012:12.

Activity of Anti–PD-1 Antibody in Patients with Treatment-Refractory
Melanoma, Non–Small-Cell Lung Cancer, or Renal-Cell Cancer.

Topalian SL et al. N Engl J Med 2012;366:2443-2454.

Activity of Anti–PD-L1 Antibody in Patients with
Advanced Melanoma and Non–Small-Cell Lung Cancer.

Brahmer JR et al. N Engl J Med 2012;366:2455-2465.

J Clin Oncol 32. 2014

Lung Cancer Response to anti-PD-1 MoAb
(Nivolumab)
Metastatic squamous cell ca; single dose of nivolumab on 5/3/2013.

April 24, 2013

Apr 17, 2014

Personal communication: Dr. R. Pillai

Relationship between PD-L1 Expression and response rates
in lung cancer

PD-L1 Negative
Response Rate: 7%

Weak Positive
(1-49%)

Strong Positive
(50-100%)

15%
Gandhi L. AACR 2014 Abstract CT 105.

37%

Increased CD8 T cell proliferation of after anti PD1
treatment in lung cancer patients
Cycle1

Cycle2

P11

P14
PD-1
Ki67

Personal communication: Dr. R. Pillai

Cycle3

Comparison of differentMonit. 2014; 20: 953 cellular therapies
anti-cancer
Zang, Med Sci

Car-T cell technology
• Identify Tumor Antigen
• Develop Monoclonal
Antibody
• Clone single chain antibody
fused to TCR signaling
• Isolate T cell from Patient
• Transfect T-cells with CAR
construct
Brown 2015 The Scientist

• Reinfuse expanded CART-T
into patient

CAR autologous T-cell immunotherapy in CLL

Porter DL et al. 2011 N Engl J Med. 365:725-733.

Inflammatory cytokines induced after CAR
autologous T-cell immunotherapy in CLL

Porter DL et al. 2011. N Engl J Med. 365:725-733.

Expansion and Persistence of Chimeric Antigen
Receptor T Cells In Vivo.

Porter DL et al. 2011. N Engl J Med. 365:725-733.

CAR-T evolution

Brown 2015 The Scientist

Recent IPO for CAR-T
Company

Date

Kite Pharma
Bellicum
Juno
Cellectis

6-2014
12-2014
12-2014
3-2015

Value (Millions)
$134.1
$160
$264.6
$228

Effect of blocking VIP signaling on
adaptive anti-viral immunity
Hypothesis: Blocking VIP signaling is predicted to
augment the magnitude of the adaptive immune
response
Model systems: Murine CMV infection, VIP
knock-out mice and wild-type mice treated with
a peptide antagonist to VIP (VIPhyb).

Structural model of VPAC1 receptor and
docking of VIP

Couvineau and Laburthe 2002 Br. J. Pharm

VIP Antagonism
N Term HSDAVFTDNYTRLRKQMAVKKYLNSILN C Term
N Term KPRRPYTDNYTRLRKQMAVKKYLNSILN C Term

• VIPhyb hybrid peptide

– Neurotensin residues modify the N-terminus

• Competes with VIP for receptors

Peptide Structures

VIP

VIPhyb

VIP inhibits T-cell proliferation in MLR

Reema Panjwani, unpublished

Con MLR

VIP 0.3 uM

VIP 1 uM

VIP 3 uM

VIP 10 uM

Stimulators

Responders

Mixed lymphocyte reaction, luciferase+ T-cells

VIP antagonists restore T cell proliferation in one-way
MLR in vitro

Reema Panjwani,
unpublished

Effect of blocking VIP signaling on anticancer immunity
Hypothesis: Short-term pharmacological
blockade of VIP-signaling will enhance the GvL
effect of donor T-cells in mouse models of
allogeneic bone marrow transplantation
Model systems: MHC mis-matched murine BMT
with luciferase+ ALL and AML cell lines

VIP is synthesized by T cells and dendritic
cells after allogeneic transplant

Jian-Ming Li,
unpublished

Treatment with VIPhyb augmented GvL activity of donor
T cells against acute myeloid leukemia

B10.BRB6 + C1498

P