Immunological checkpoints and cancer immunotherapy were reviewed. Immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1 antibodies can activate the immune system against cancer by blocking inhibitory signals to T cells. Clinical trials show these drugs produce durable responses in various cancers like melanoma, lung cancer, and Merkel cell carcinoma. Combining different immunotherapies or with other treatments may help more patients by overcoming resistance. Ongoing research aims to better understand combination approaches and biomarkers of response.
Call Girls in Lucknow Just Call 👉👉7877925207 Top Class Call Girl Service Avai...
Immunological Checkpoints and Cancer Immunotherapy
1. Immunological Checkpoints and Cancer Immunotherapy:
Review of Data and Issues of Interest for Imaging Community
Elad Sharon, MD, MPH
Senior Investigator/Medical Officer
Cancer Therapy Evaluation Program
Division of Cancer Therapy & Diagnosis
National Cancer Institute
August 7, 2017
3. Options for Immune Intervention in Cancer
Vaccines (induce immune response against presumed cancer antigen)
Defined antigen and delivery method
Promote Ag presentation in vivo
Cytokines to promote T-cell activation, proliferation and function
Provide T cell co-stimulatory signals
Block T cell inhibitory signals
Adoptively transfer antigen-specific T cells
Bispecific antibodies
Give antibodies that kill by CDC or ADCC
Activate NK cell function to kill tumor cells
4. Atkins, M. B. Clin Cancer Res 2006;12:2353s-
2358s
High Dose IL-2: Durable Responses
• RR: 16% (43/270)
• CR: 6.2%
• Durable responses
– Median 8.9
mos
– CR: not reached
Fyfe G, et al. J Clin Oncol. 1995;13:688-696
Melanoma Renal Cell
Carcinoma
5. Chen and Mellman. Immunity 2013
Killing of cancer cells
Anti-PD-L1
Anti-PD-1
IDO inhibitors
Priming and activation
Anti-CTLA4
Anti-CD137 (agonist)
Anti-OX40 (agonist)
Anti-CD27 (agonist)
IL-2
IL-12
Cancer antigen
presentation
Vaccines
IFN-α
GM-CSF
Anti-CD40 (agonist)
TLR agonists
Release of
cancer cell antigens
Chemotherapy
Radiation therapy
Targeted therapy
Recognition of
cancer cells by T cells
CARs
TCRs
TILs
Infiltration of T cells
into tumours
Anti-VEGF
Trafficking of
T cells to tumours
tumour
The Cancer-Immunity Cycle
6. Key Features of Immune Checkpoint Inhibitors
Associated with immune-related adverse events
Any organ, but rash, colitis, hepatitis and endocrinopathies are most common
May require steroids +/- additional immunosuppressive agents
Unique kinetics of response in some patients
Responses may improve with time
Occasional responses after initial increase in total tumor volume
Response in index plus new lesions at or after the appearance of new lesions
Continued benefit after therapy of discordant progressing lesions
7. Biological Function and Details of CTLA-4
CTLA-4 is (almost) exclusively on T cells
Primarily regulates the amplitude of the early stages of T-cell activation
CTLA-4 knockout mice die within 3 weeks from immune destruction of multiple
organs
CTLA-4 counteracts the activity of the T cell costimulatory receptor CD28
CD28 does not affect T-cell activation unless the TCR is first engaged by
cognate antigen
8. CD28, CTLA-4, and the TCR
CD28 signaling strongly amplifies
the TCR signal to activate T cells
CD28 and CTLA-4 share
identical ligands:
CD80 (B7.1) and CD86 (B7.2)
CTLA-4 has a much higher
overall affinity for both ligands
Studies suggest that CTLA-4
signaling disrupts kinase signals
induced by TCR and CD28
Alegre et al. Nature Reviews Immunology. 2001
9. How does CTLA-4 work?
CTLA-4 is expressed by activated CD8 killer T cells
Distinct effects on the two major subsets of CD4 T cells
• Down-modulation of helper T-cell activity
• Enhancement of regulatory T-cell suppressive activity
• CTLA-4 blockade results in a broad enhancement of immune
responses dependent on helper T cells
• CTLA-4 is a target gene of the transcription factor Foxp3, the
expression of which determines the Treg lineage
Tregs express CTLA-4 constitutively
10. Ipilimumab: The Beginning of an Era
Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone
1-yr 44% 46% 25%
2-yr 22% 24% 14%
11. Biological Function and Details of PD1
Limits activity of T cells in the peripheral
tissues at the time of an inflammatory
response to stimulus
Expression is induced when T cells become
activated
PD-1 inhibits kinases involved in T-cell
activation via the phosphatase SHP2
PD-1 is highly expressed on Tregs, where it
may enhance proliferation in the presence of
ligand
Mario Sznol, and Lieping Chen Clin Cancer Res 2013;19:1021-1034
12. Effects of Expression of PD-1
PD-1 is more broadly expressed than CTLA-4
Can be induced on B cells and NK cells
Two ligands for PD-1 are PD-L1 and PD-L2
Arose via gene duplication
Positioned them within 100 kB
Chronic antigen exposure, (including viral infections) can lead to high levels of
persistent PD-1 expression, which induces a state of exhaustion or anergy
among cognate antigen-specific T cells
PD-1 can also shift the balance from T-cell activation to tolerance at early
stages in T-cell responses to antigen within secondary lymphoid tissues
Pardoll DM. Seminars in Oncology. 2015
13. PD-1 Expression in the Tumor Microenvironment
PD-1 expressed on a large number of TILs in many tumor types
Tregs can be a large fraction
Expression on CD8 TILs may reflect an anergic/exhausted state (e.g.
decreased cytokine production)
Primary PD-1 role is inhibition in the tumor microenvironment
• Inhibition only occurs with cognate ligand
PD-L2 has also been reported to be upregulated on a number of tumors
Upregulated on certain B-cell lymphomas
14. 45%
Type 1
17%
Type 2
26%
Type 3
12%
Type 4
Presence of PD-L1 or TILs1
PD-L1/TIL
PPD-L1 /TIL+
D-L1 /TIL+
PD-L1/TIL PD-L1+/TIL+
PD-L1 /TIL+ PD-L1+/TIL
45%
Type 1
17%
Type 2
26%
Type 3
12%
Type 4NSCLC
Melanoma 45% 41% 13% 1%
Schalper &
Rimm, Yale U.
Taube et
al
15. Spectrum of PD-1/PD-L1 Antagonist Activity
Melanoma
Renal cancer (clear cell and non-clear cell)
NSCLC – adenocarcinoma and squamous cell
Head and neck cancer
Hodgkin Lymphoma
Bladder Cancer
Merkel Cell
Mismatch repair deficient tumors
Small cell lung cancer
Gastric and GE junction
Triple negative breast cancer
Ovarian
Hepatocellular carcinoma
Mesothelioma
Nasopharyngeal Cancer
Cervical
Diffuse large B-cell lymphoma
Follicular lymphoma
Major PD-1/PD-L1 antagonists
• Nivolumab (anti-PD-1)
• Pembrolizumab (anti-PD-1)
• Atezolizumab (MPDL3280A, anti-PD-L1)
• Durvalumab (MEDI-4736, anti-PD-L1)
• Avelumab (anti-PD-L1)
• Other PD-1 efforts ongoing from:
• CureTech/Medivation (CT-011)
• Sanofi/Regeneron (REGN2810)
• Novartis (PDR001)
• Aurigene/Pierre Fabre (AUNP-12)
Minimal to no activity to single agents:
• Prostate cancer
• Microsatellite Stable Colon cancer
• Multiple Myeloma
• Pancreatic Cancer
Active
20. 20
Use Case: How PD1/PDL1
Inhibitors Have Performed in
Merkel Cell Cancer
21. Epidemiology
About 1600 new cases per year in USA
Increasing incidence (tripled in past 15 years)
Uncommon cutaneous malignancy with epithelial and neuroendocrine
features
Found on UV exposed areas
Median age 76
More common in Caucasians and males
High risk of developing nodal and distant metastases
Overall mortality of 45%
1. Youlden DR et al. JAMA Dermatol. 2014;150:864-872.
22. Merkel Cell Polyomavirus
Identified in 2008 at U of Pittsburgh
Highly prevalent in normal skin
One of 13 known human polyomaviruses
Virus present in approximately 80% of MCC tumor DNA
Serum antibodies to MCPyV T-antigens more specifically associated
with MCC
1. Feng H et al. Science. 2008;319:1096-1100.
2. Moshiri AS, Nghiem P. J Natl Compr Canc Netw. 2014;12:1255-1262.
3. Grundhoff A, Fischer N. Curr Opin Virol. 2015;14:129-137.
31. Waterfall plot: Pembrolizumab Responses in virus-pos &
virus-neg MCCs
-
40
-
80
Maximum Change In Sum of Target Lesion Diameters
PercentChangeinTargetLesions
-100-60-20020406080
(N=24)
Viral Status
Negative
Positive
100120140160
Percentchangeintargetlesions Tumor viral status
negative
positive
n = 24
Fraction responding:
44% of virus-neg
62% of virus-pos
(difference not significant)
32. Pembrolizumab Swimmer plot: most responses persist
Months from treatment initiationMonths from Treatment Initiation
0 2 4 6 8 10 12 14
➔
➔
Complete Response
Partial Response
Stable Disease
Progressive Disease
Ongoing CR
Ongoing PR
On Treatment
Most responses
are durable
(86%; 12 of 14
confirmed
responses persist)
Even 1-2 doses
of anti-PD-1 can
induce sustained
response
33. Baseline 3 wks after
pembrolizumab
Pembrolizumab Case example: partial response
After 1 dose:
SQ lesion barely palpable at 3 weeks;
biopsy showed. . .
Primary on R knee...10 mo later
Bulky tumors in pelvis: bladder compression
Subcutaneous metastases on leg
34. Baseline 12 weeks
Pembrolizumab Partial response on anti-PD-1
Bulky pelvic disease
Bladder symptoms resolved
Therapy & response ongoing (13 months)
No side effects
Tumors continue to shrink
36. Responses with Pembrolizumab with
PD-L1 positive / negative tumors
Months from treatment initiation
PercentChangeinTarget
Lesions
Tumor PD-L1 status
negative
positive
n = 23
37. Goh et al. Oncotarget 2015.
MCPyV positive vs.
negative MCC: at the
extremes of
mutational frequency
compared to TCGA
data for other
cancers
Virus Positive Virus Negative
UVmutations
38. Goh et al, Oncotarget 2015
Virus-negative MCCs high mutational load and many
predicted neoantigens
39. Conclusions
• Anti-PD-1/PDL-1 induces a high response rate in a rare tumor in the
metastatic setting, both frontline and relapsed
• Responses in both virus positive and virus negative MCC
• Encouraging response durability
• Correlative studies are ongoing for anti-MCPyV antibody and T cell
responses
• Expansion of pembrolizumab trial ongoing
• Further efforts are necessary to reduce relapse at earlier settings of
disease to improve overall survival
44. How to Establish Efficacy
Use of poor endpoints can be just as problematic in immuno-oncology
drug development as in all other parts of drug development
Single arm PFS or OS trials can be subject to significant bias as a result of
patient selection
Trials in general involve a “sample” of the total cancer population – samples
can be misleading…
Recommend discrete, measurable and definitive endpoints
Randomized trials: OS, PFS, Response Rate, pCR
Single arm trials: Some proxy for biologic activity – Response Rate, pCR
TCR Analysis and Changes in Repertoire? TILs?
46. Issues for the Immunotherapy Community
iRECIST and related immunologically-modified Imaging Response
Criteria
Pseudoprogression
Novel Imaging Problems
Hyperprogression
Novel Imaging Products
Imaging T cells by PET
Imaging radiolabeled PDL1
Radiomics
47. iRECIST, irRECIST, iChesson, irRC
Alphabet soup of new imaging criteria for immunotherapy
What is the point?
Will this help patients, or patient management?
Does this involve lowering the bar for efficacy?
Does iPFS better predict OS than current standards?
48.
49. Hyperprogression
Does it exist?
Is there a tendency to overcall hyperprogression?
How to prove it?