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Immunotherapy 101
Claire Friedman
10/8/15
Let’s take a step back…
• To basic immunology!
• T cells
– Two main subsets: CD4+ (helper) and CD8+ (effector)
– CD4+ cell...
T cells
• Cytotoxic T cells
– Upon activation can proliferate and directly kill
infected or cancerous cells
– Activation r...
Antigen Presenting Cells
• Cells that display foreign antigens complexed
with MHCs
• Examples: Dendritic cells, macrophage...
Cancer and the immune system
• Our immune system is constantly looking for
abnormal cells and destroying them
– It’s calle...
Tumor Intrinsic Factors
• Antigen Loss or MHC loss
• Secretion of immunosuppressive cytokines
• Expression of cell-surface...
Tumor Extrinsic Factors
• Geographic barriers
• Suppressive or regulatory immune cells
– Tregs
– Myeloid derived suppresso...
So, where do we go from here?
• How can we train our immune systems to
overcome both types of resistance?
Driving the T cell
T cells have both a gas pedal and a brake pedal (otherwise
known as activating receptors and inhibitor ...
Ipilimumab AugmentsT-Cell Activation and Proliferation
Adapted from O’Day et al. Plenary session presentation, abstract #4...
Immune-RelatedAdverse Events
• Rash (approx 20%)
• Colitis/enteritis (approx 15%)
• Elevated AST/ALT (approx 10%)
• Endocr...
Ipilimumab Pattern of Response:
Responses After the Appearance and Subsequent Disappearance of
New Lesions
3 mg/kg
ipilimu...
irRC Identifies Survivors in Patients with Progressive Disease
by mWHO
Pooled data from phase II studies CA184-008 and CA1...
Patients at Risk
Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36...
MHC
PD-L1
PD-1 PD-1
PD-1 PD-1
Nivolumab, Pembrolizumab:
PD-1 Receptor Blocking Abs
Recognition of tumor by T cell through
...
Tumor Burden in Patients with Melanoma Receiving Nivolumab
19
Vertical line at 96 weeks = maximum duration of continuous n...
Georgina V. Long, Victoria Atkinson, Paolo A. Ascierto, Benjamin Brady,
Caroline Dutriaux, Michele Maio, Laurent Mortier, ...
Phase 3 CA209-066: Study Design
*Patients may be treated beyond initial RECIST v1.1-defined progression if considered by t...
Best Overall Response
Nivolumab
(N = 210)
Dacarbazine
(N = 208)
ORR, % (95% CI) 40% (33–47%) 14% (10–19%)
Best overall res...
0 3 6 9 12 15 18
Primary Endpoint: Overall Survival
Patients who died,
n/N
Median OS
mo (95% CI)
Nivolumab 50/210 NR
Dacar...
Improved OS irrespective of PD-L1 status
OS by PD-L1 Status*
100
90
80
70
60
0
50
40
30
20
10
0 3 6 9 12 15 18
Months
Nivo...
KEYNOTE-006 (NCT01866319):
International, Randomized, Phase III Study
Patients
• Unresectable, stage III or IV
melanoma
• ...
0 2 4 6 8 10 12 14
0
10
20
30
40
50
60
70
80
90
100
Time, months
Progression-FreeSurvival,%
No. at risk
279 231 147 98 49 ...
0 2 4 6 8 10 12 14 16 18
30
40
50
60
70
80
90
100
Time, months
OverallSurvival,%
No. at risk
279 266 248 233 219 212 177 6...
What about other malignancies
besides melanoma?
Ansell SM et al. N Engl J Med 2015;372:311-319.
Response Characteristics and Changes in Tumor Burden in Patients with Hodg...
Brahmer J et al. N Engl J Med 2015;373:123-135.
Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-...
Motzer RJ et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1510665
Nivolumab vs Everolimus for the treatment of metastatic RCC
Blocking CTLA-4 and PD-1
T cell
Tumor cell
MHC
TCR
PD-L1PD-1
- - -
T cell
Dendritic
cell
MHC
TCR
CD28
B7 CTLA-4
- - -
Acti...
Larkin J et al. N Engl J Med 2015;373:23-34.
Nivolumab vs ipilimumab vs combination therapy in patients with metastatic
me...
Larkin J et al. N Engl J Med 2015;373:23-34.
Tumor-Burden Change in Target Lesions.
Where do we go from here?
• Combination immunotherapy in other disease
areas (AML, CLL, head and neck)
• Other checkpoint ...
Questions?
Immunotherapy 101
Immunotherapy 101
Immunotherapy 101
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Immunotherapy 101

  1. 1. Immunotherapy 101 Claire Friedman 10/8/15
  2. 2. Let’s take a step back… • To basic immunology! • T cells – Two main subsets: CD4+ (helper) and CD8+ (effector) – CD4+ cells can be broken down further into Th1, Th2 and Treg – Th1 : proinflammatory, stimulated by IFN-ɣ, support anti-viral and anti-tumor responses. – Th2: anti-inflammatory, associated with secretion of IL-10. Favor anti-parasitic responses. – T reg: Inhibit and dampen immune response
  3. 3. T cells • Cytotoxic T cells – Upon activation can proliferate and directly kill infected or cancerous cells – Activation requires two signals: One from an APC, one from a costimulatory molecule such as CD28 • Helper T cells – Facilitate a coordinated immune response – Can differentiate down a number of pathways based on the cytokine milieu
  4. 4. Antigen Presenting Cells • Cells that display foreign antigens complexed with MHCs • Examples: Dendritic cells, macrophages, some B-cells • Can interact with T cells via the T cell receptor and direct the pathway of the T cell
  5. 5. Cancer and the immune system • Our immune system is constantly looking for abnormal cells and destroying them – It’s called tumor necrosis factor (TNF) for a reason • So how does cancer evade this surveillance?
  6. 6. Tumor Intrinsic Factors • Antigen Loss or MHC loss • Secretion of immunosuppressive cytokines • Expression of cell-surface markers such as programmed death ligand 1 (PD-L1) that alter T cell function • Like the invisibility cloak from Harry Potter
  7. 7. Tumor Extrinsic Factors • Geographic barriers • Suppressive or regulatory immune cells – Tregs – Myeloid derived suppressor cells (MDSCs) – Tumor-associated macrophages (TAMs)
  8. 8. So, where do we go from here? • How can we train our immune systems to overcome both types of resistance?
  9. 9. Driving the T cell T cells have both a gas pedal and a brake pedal (otherwise known as activating receptors and inhibitor receptors) (Mellman I., Coukos G., and Dranoff G. Nature.2011;480(7378):480-9)
  10. 10. Ipilimumab AugmentsT-Cell Activation and Proliferation Adapted from O’Day et al. Plenary session presentation, abstract #4, ASCO 2010. T-cell APC TCR HLA CD80/ CD86 T-cell inhibition CTLA-4 CD28 T-cell APC TCR HLA T-cell activation CD28TCR HLA T-cell APC CD80/ CD86 T-cell remains active Ipilimumab blocks CTLA-4 T-cell APC CTLA-4 CD80/ CD86 TCR HLA
  11. 11. Immune-RelatedAdverse Events • Rash (approx 20%) • Colitis/enteritis (approx 15%) • Elevated AST/ALT (approx 10%) • Endocrinopathies: Thyroiditis, Hypophysitis, Adrenal insufficiency(2-5%) Severity is inversely related to vigilance of surveillance. If detected early, most are easily treated and reversible.
  12. 12. Ipilimumab Pattern of Response: Responses After the Appearance and Subsequent Disappearance of New Lesions 3 mg/kg ipilimumab Q3W X 4 Pre-treatment Week 36: Still Regressing Week 12: Progression Week 20: Regression New lesions Source: 2008 ASCO Abstract #3020 Wolchok. July 2006
  13. 13. irRC Identifies Survivors in Patients with Progressive Disease by mWHO Pooled data from phase II studies CA184-008 and CA184-022: ipilimumab monotherapy 10 mg/kg (N=227) Wolchok et al, Clin Cancer Res, 2009
  14. 14. Patients at Risk Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 84 96 108 120 Ipilimumab CENSORED Ipilimumab LongTerm Pooled Survival Analysis: 4846 Patients Median OS (95% CI): 9.5 (9.0–10.0) 3-year OS Rate (95% CI): 21% (20–22%) ProportionAlive Months Schadendorf, Hodi Wolchok, ESMO, 2013
  15. 15. MHC PD-L1 PD-1 PD-1 PD-1 PD-1 Nivolumab, Pembrolizumab: PD-1 Receptor Blocking Abs Recognition of tumor by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 up-regulation on tumor Priming and activation of T cells through MHC/antigen & CD28/B7 interactions with antigen-presenting cells T-cell receptor T-cell receptor PD-L1 PD-L2 PD-L2 MHC CD28 B7 T cell NFκB Other PI3K Dendritic cellTumor cell IFNγ IFNγR Shp-2 Shp-2 Role of PD-1 Pathway inTumor Immunity 18 Sznol et al., ASCO, 2013
  16. 16. Tumor Burden in Patients with Melanoma Receiving Nivolumab 19 Vertical line at 96 weeks = maximum duration of continuous nivolumab therapy Horizontal line at −30% = threshold for defining objective response (partial tumor regression) in absence of new lesions or non-target disease according to RECIST Unconventional response = response patterns that did not meet RECIST criteria (e.g., persistent reduction in target lesions in the presence of new lesions, or regression following initial progression) All Mel patients treated with 3 mg/kg nivolumab 4 Mel patients treated with unconventional responses from nivolumab 1st occurrence of new lesion 3 mg/kg Weeks since treatment initiation Changeintargetlesionsfrombaseline(%) 1st occurrence of new lesion Weeks since treatment initiation Changeintargetlesionsfrombaseline(%) 1 mg/kg 1 mg/kg1 mg/kg 10 mg/kg Sznol et al., ASCO, 2013
  17. 17. Georgina V. Long, Victoria Atkinson, Paolo A. Ascierto, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Kerry J. Savage, Micaela Hernberg, Celeste Lebbé, Julie Charles, Catalin Mihalcioiu, Vanna Chiarion-Sileni, Cornelia Mauch, Henrik Schmidt, Dirk Schadendorf, Helen Gogas, Christine Horak, Brian Sharkey, Ian Waxman, Caroline Robert Nivolumab Improved Survival vs Dacarbazine in Patients with Untreated Advanced Melanoma
  18. 18. Phase 3 CA209-066: Study Design *Patients may be treated beyond initial RECIST v1.1-defined progression if considered by the investigator to be experiencing clinical benefit and tolerating study drug Treat until progression* or unacceptable toxicity Primary endpoint: • OS Secondary endpoints: • PFS • ORR • PD-L1 correlates R 1:1 Nivolumab 3 mg/kg IV Q2W + Placebo IV Q3W N=210 (206 treated) Placebo IV Q2W + Dacarbazine 1000 mg/m2 IV Q3W N=208 (205 treated) Double- blind Eligible patients with unresectable stage III or IV melanoma (N=418) • BRAF wild-type • Treatment-naïve Stratified by: • PD-L1 status (≥ 5% cell-surface staining cutoff) • M-stage
  19. 19. Best Overall Response Nivolumab (N = 210) Dacarbazine (N = 208) ORR, % (95% CI) 40% (33–47%) 14% (10–19%) Best overall response Complete response 8% 1% Partial response 32% 13% Stable disease 17% 22% Progressive disease 33% 49% Unable to determine 11% 15% Based on 5 August 2014 database lock.
  20. 20. 0 3 6 9 12 15 18 Primary Endpoint: Overall Survival Patients who died, n/N Median OS mo (95% CI) Nivolumab 50/210 NR Dacarbazine 96/208 10.8 (9.3–12.1) NR = not reached. Based on 5 August 2014 database lock. 100 90 80 70 60 0 50 40 30 20 10 HR 0.42 (99.79% CI, 0.25–0.73; P < 0.0001) (Boundary for statistical significance 0.0021) 210 208 185 177 150 123 105 82 45 22 8 3 0 0 Nivolumab (N = 210) Dacarbazine (N = 208) Months PatientsSurviving(%) 1-yr OS 73% 1-yr OS 42% Patients at Risk Nivolumab Dacarbazine Follow-up since randomization: 5.2–16.7 months.
  21. 21. Improved OS irrespective of PD-L1 status OS by PD-L1 Status* 100 90 80 70 60 0 50 40 30 20 10 0 3 6 9 12 15 18 Months Nivolumab PD-L1+ Dacarbazine PD-L1+ Nivolumab PD-L1- Dacarbazine PD-L1- Patients at Risk Dacarbazine PD-L1- Nivolumab PD-L1- Dacarbazine PD-L1+ Nivolumab PD-L1+ 74 128 74 126 69 108 64 107 56 88 44 78 39 63 30 52 18 26 11 11 1 7 1 2 0 0 0 0 PatientsSurviving(%) 1-Yr OS % (95% CI) 82.1 (69.6–89.8) 67.8 (58.3–75.7) 52.7 (37.7–65.7) 37.4 (26.4–48.3) Patients who died, n/N Median OS mo (95% CI) Nivolumab PD-L1+ 11/74 NR Nivolumab PD-L1- 37/128 NR Dacarbazine PD-L1+ 29/74 12.4 (9.2–NR) Dacarbazine PD-L1- 64/126 10.2 (7.6–11.8) *PD-L1 positive: ≥ 5% tumor cell surface staining. PD-L1 negative: < 5% tumor cell surface staining. NR=not reached. Based on 5 August 2014 database lock.
  22. 22. KEYNOTE-006 (NCT01866319): International, Randomized, Phase III Study Patients • Unresectable, stage III or IV melanoma • ≤1 prior therapy, excluding anti– CTLA-4, PD-1, or PD-L1 agents • Known BRAF statusa • ECOG PS 0-1 • No active brain metastases • No serious autoimmune disease Pembrolizumab 10 mg/kg IV Q2W Pembrolizumab 10 mg/kg IV Q3W R 1:1:1 Stratification factors: • ECOG PS (0 vs 1) • Line of therapy (first vs second) • PD-L1 status (positiveb vs negative) Ipilimumab 3 mg/kg IV Q3W x 4 doses aPrior anti-BRAF targeted therapy was not required for patients with normal LDH levels and no clinically significant tumor-related symptoms or evidence of rapidly progressing disease. bDefined as membranous PD-L1 expression in ≥1% of tumor cells as assessed by IHC using the 22C3 antibody. • Primary end points: PFS and OS • Secondary end points: ORR, duration of response, safety
  23. 23. 0 2 4 6 8 10 12 14 0 10 20 30 40 50 60 70 80 90 100 Time, months Progression-FreeSurvival,% No. at risk 279 231 147 98 49 7 2 0 277 235 133 95 53 7 1 1 278 186 88 42 18 2 0 0 PFS at Interim Analysis 1 (IA1) Analysis cut-off date: September 3, 2014. Median (95% CI), mo Rate at 6 mo HR (95% CI) P 5.5 (3.4-6.9) 47.3% 0.58 (0.46-0.72) <0.00001 4.1 (2.9-6.9) 46.4% 0.58 (0.47-0.72) <0.00001 2.8 (2.8-2.9) 26.5% — — Pembrolizumab Q2W Pembrolizumab Q3W Ipilimumab
  24. 24. 0 2 4 6 8 10 12 14 16 18 30 40 50 60 70 80 90 100 Time, months OverallSurvival,% No. at risk 279 266 248 233 219 212 177 67 277 266 251 238 215 202 158 71 278 242 212 188 169 157 117 51 19 18 17 0 0 0 OS at the Second Interim Analysis (IA2) Analysis cut-off date: March 3, 2015. Treatment Arm Median (95% CI), mo Rate at 12 mo HR (95% CI) P Pembrolizumab Q2W NR (NR-NR) 74.1% 0.63 (0.47-0.83) 0.00052 Pembrolizumab Q3W NR (NR-NR) 68.4% 0.69 (0.52-0.90) 0.00358 Ipilimumab NR (12.7-NR) 58.2% — —
  25. 25. What about other malignancies besides melanoma?
  26. 26. Ansell SM et al. N Engl J Med 2015;372:311-319. Response Characteristics and Changes in Tumor Burden in Patients with Hodgkin's Lymphoma Receiving Nivolumab.
  27. 27. Brahmer J et al. N Engl J Med 2015;373:123-135. Efficacy of Nivolumab versus Docetaxel in Patients with Advanced Squamous-Cell Non– Small-Cell Lung Cancer.
  28. 28. Motzer RJ et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1510665 Nivolumab vs Everolimus for the treatment of metastatic RCC
  29. 29. Blocking CTLA-4 and PD-1 T cell Tumor cell MHC TCR PD-L1PD-1 - - - T cell Dendritic cell MHC TCR CD28 B7 CTLA-4 - - - Activation (cytokines, lysis, proliferation, migration to tumor) B7 +++ +++ CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab) anti-CTLA-4 anti-PD-1 Tumor Microenvironment +++ PD-L2PD-1 anti-PD-1 - - -
  30. 30. Larkin J et al. N Engl J Med 2015;373:23-34. Nivolumab vs ipilimumab vs combination therapy in patients with metastatic melanoma: progression-free survival.
  31. 31. Larkin J et al. N Engl J Med 2015;373:23-34. Tumor-Burden Change in Target Lesions.
  32. 32. Where do we go from here? • Combination immunotherapy in other disease areas (AML, CLL, head and neck) • Other checkpoint antibodies (LAG3, GITR, OX40) alone and in combination with PD-1 • Checkpoint inhibitors in combination with therapeutic vaccines (Ty-Vec with anti-PD-1)
  33. 33. Questions?

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