This document summarizes a presentation on new immunotherapies for cancer treatment. It discusses the discovery of immune checkpoint proteins like CTLA-4 and PD-1, and the development of immune checkpoint inhibitor drugs like Ipilimumab, Pembrolizumab and Nivolumab. It describes clinical trials that demonstrated the effectiveness of these drugs, particularly Ipilimumab, in treating melanoma. The document outlines the mechanisms of action of these drugs in overcoming immune suppression by tumors and restoring anti-tumor immune responses.
9. The goal of cancer immunotherapy is
to boost or restore the ability of the
immune system to detect and destroy
cancer cells by overcoming the
mechanisms by which tumors evade
and suppress the immune response,
Disis ML, Semin Oncol, 2014
10. The goal of cancer immunotherapy is
to boost or restore the ability of the
immune system to detect and destroy
cancer cells by overcoming the
mechanisms by which tumors evade
and suppress the immune response,
Disis ML, Semin Oncol, 2014
25. La activación del linfocito T (cebamiento o priming) reqiere de las dos sinapsis CO-
ESTIMULATORIAS: MHCII-TCR (con presentación de antígeno) y CD80 (u CD86)-
CD28
31. The primary role of immune
checkpoints is to protect tissues from
damage when the immune system is
responding to pathogens and to
maintain tolerance to self-antigens (ie,
prevent autoimmunity). This is
primarily achieved by downregulating
T-cell activation or effector functions
Disis ML, Semin Oncol, 2014
32. The primary role of immune
checkpoints is to protect tissues from
damage when the immune system is
responding to pathogens and to
maintain tolerance to self-antigens (ie,
prevent autoimmunity). This is
primarily achieved by downregulating
T-cell activation or effector functions
Disis ML, Semin Oncol, 2014
33. James Allison
Professor, Chair of Immunology
M.D. Anderson Cancer Center
Houston, Texas
Nobel Prize Medicine and Physiology - 2018
CTLA-4 was a brake
Protein structure of
the T-Cell receptor
(M.D. Anderson)
Born 1948, Alice, Tx
Co-stimulatory
signal
CD28
CTLA-4 and CD28
shared the same ligands
(B7-1, B7-2
in dendritic cells)
“((in cancer))… this all starts a
negative program as well by inducing
thE CLKA-4 gene, and that’s what’s
going to eventually turn the system
off.”
“I proposed treating cancer by ignoring it.”
39. James Allison
Professor, Chair of Immunology
M.D. Anderson Cancer Center
Houston, Texas
Nobel Prize Medicine and Physiology - 2018
Search for a biotech
company interested in
an anti-CTLA-4 in cancer
Born 1948, Alice, Tx
Medarex synthesis
of Ipilimumab
“medarex thought that mdx-010
was an activating molecule”
43. James Allison
Professor, Chair of Immunology
M.D. Anderson Cancer Center
Houston, Texas
Nobel Prize Medicine and Physiology - 2018
Clinical Trials
Melanoma
Search for a biotech
company interested in
an anti-CTLA-4 in cancer
Born 1948, Alice, Tx
Medarex synthesis
of Ipilimumab
Phase I trial
of Ipi: 3 objective
responses
44. Jedd Wolchok
First clinical trials with
Ipilimumab by
MSKCC/Medarex
Worked in immunology
with Dr. Houghton
(MSKCC)
Born 1965, Staten Island, NY
Heard about Allison’s
anti-CTLA-4 ab
45. Jedd Wolchok
Chief, Melanoma and Immunotherapeutics Service
Memorial Sloan Kettering Cancer Center
New York, New York
First clinical trials with
Ipilimumab by
MSKCC/Medarex
Worked in immunology
with Dr. Houghton
(MSKCC)
Born 1965, Staten Island, NY
Heard about Allison’s
anti-CTLA-4 ab
Despite the bad test results, the patient said he felt better
Initial studies looked for
Response Rates using
RECIST
One patient with
melanoma had
progressed, by
RECIST, but said “I feel
better”
That same patient came
back with LESS disease
46. Jedd Wolchok
Chief, Melanoma and Immunotherapeutics Service
Memorial Sloan Kettering Cancer Center
New York, New York
Born 1965, Staten Island, NY
Despite the bad test results, the patient said he felt better
For Phase III trial the CHOSEN
primary endpoint was Overall
Survival, not PFS
Precedent: Another anti-CTLA-4
(tremelimumab) chose PFS as the primary
endpoint, and the trial was negative
47. Clinical Trials
Melanoma
Search for a biotech
company interested in
an anti-CTLA-4 in cancer
James Allison, MD Anderson/MSKCC
Medarex synthesis
of Ipililimumab
Phase I trial
of Ipi: 3 objective
responses
Jedd Wolchok, MSKCC Axel Hoos, BMS
49. Clinical Trials
Melanoma
Search for a biotech
company interested in
an anti-CTLA-4 in cancer
James Allison, MD Anderson/MSKCC
Medarex synthesis
of Ipililimumab
Phase I trial
of Ipi: 3 objective
responses
FDA approval of
Ipilimumab
in Metastatic Melanoma
(2011)
Jedd Wolchok, MSKCC Axel Hoos, BMS
55. Tasuku Honjo
Professor, Department of Immunology
and Genomic Medicine
Kyoto University
Kyoto, Japan
PD-1Worked in AICDA
Born 1942, Kyoto, Japan
Looking for thymic
Selection mechanisms
Curiosity, a challenge, and courage… patience
Knock-out (PD-1) mice
Unlike CTLA-4 mice,
PD-1 mice did survive
After a while… PD-1
mice developed
diseases…
2002
1994
PD1 is broadly expressed: T-Cells, B-Cells, NK-Cells
57. El PD-L1 (PD-L2) se
expresa en las
células bajo el
influjo continuo de
interferón gamma
Célula
tumoral
Linfocito T
CD8+/Citotóxico
IFN-γ
IFN-γR
PD-L1
PD-1
- - -
La sinapsis PD1/PD-L1
Inhibe al linfocito T citotóxico
77. Survival
Time
Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
Survival Pattern with Chemotherapy and Immune
checkpoint blockade
Chemotherapy
78. Survival
Time
Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
Survival Pattern with Chemotherapy
ICI
Chemotherapy
ICI: Immune checkpoint inhibitor
82. Key Eligibility
Criteria
Untreated stage IV
NSCLC
No sensitizing EGFR
or ALK alteration
ECOG PS 0 or 1
PD-L1 ≥ 50%
No symptomatic brain
metastases
No significant
glucocorticoid or
immunosuppressive
therapy
Platinum-based chemotherapy
Q3W for 4 x 6 cycles
Pembrolizumab 200 mg
Q3W for 35 cycles
Pemetrexed maintenance,
allowed
Pembrolizumab
200 mg Q3W
for up to 35 cycles
R
1:1
On PD
Reck M, NEJM, 2016
KEYNOTE-024
84. Key Eligibility
Criteria
Untreated stage IV
nonsquamous NSCLC
No sensitizing EGFR
or ALK alteration
ECOG PS 0 or 1
Provision of a sample
for PD-L1 assessment
No symptomatic brain
metastases
No pneumonatisi
requiring systemic
steroids
Placebo (normal saline) +
Pemetrexed 500 mg/m2 +
Carboplatin AUC 5 OR
Cisplatin 75 mg/m2
Q3W for 4 cycles
Pembrolizumab 200 mg +
Pemetrexed 500 mg/m2 +
Carboplatin AUC 5 OR
Cisplatin 75 mg/m2
Q3W for 4 cycles
Pembrolizumab 200 mg Q3W for
up to 31 cycles
+
Pemetrexed
500 mg/m2 Q3W
Placebo (normal saline)
for up to 31 cycles
+
Pemetrexed
500 mg/m2 Q3W
Pembrolizumab
200 mg Q3W
for up to 35 cycles
R
2:1
On PD
Gandhi, AACR, 2018
KEYNOTE-189
86. Arm B
Atezolizumab +
Carboplatin + Paclitaxel
+ Bevacizumab
4 or 6 cycles
Atezolizumab
+
Bevacizumab
Arm C (control)
Carboplatin + Paclitaxel
+ Bevacizumab
4 or 6 cycles
Bevacizumab
Key Eligibility Criteria
Untreated stage IV or
recurrent non-
squamous NSCLC
Chemotherapy-naïve
ECOG PS 0 or 1
Provision of a sample
for PD-L1 and
biomarker assessment
R
1:1:1
Reck, ESMO, 2017
IMpower150
89. LT OS & Impact of Early Response/Disease Control With Nivolumab in 2L+ NSCLC
Figure 2. OS with nivolumab vs docetaxel in CheckMate 017/ 057a
Nivolumab
(n = 427)
Docetaxel
(n = 427)
Median OS
(95% CI), mo
11.1
(9.2, 13.1)
8.1
(7.2, 9.2)
427 264 145 84 45 34 1957 26 11 1 0
100
0
40
60
80
20
34%
14%
8%
5%
14%17%
48%
27%
427 280 205 150 84 70 55113 64 37 9 0
Nivolumab
Docetaxel
No. at risk
Nivolumab
Docetaxel
Months
0 6 18 24 30 42 48 6012 36 54 66
OS(%)
aIn the nivolumab and docetaxel arms, 4.0% (17/427) and 10.1% (43/427) of patients, respectively, received subsequent immunotherapy (includes 23 patients who crossed over from the
docetaxel arm to the nivolumab arm); 5 of 19 patients (26.3%) originally randomized to docetaxel and still alive at database lock received immunotherapy as subsequent therapy.
92. OS in PD-L1+ Population
Presented By Peter Schmid at 2019 ASCO Annual Meeting
93. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous
stem-cell transplantation and brentuximab vedotin: a multicentre,
multicohort, single-arm phase 2 trial.
Younes A, Lancet Oncol, 2016
95. Advanced Melanoma
945 previously untreated patients
with unresectable stage III or IV
melanoma to nivolumab alone,
nivolumab plus ipilimumab, or
ipilimumab alone. Progression-free
survival and overall survival were
coprimary end points.
Larkin J, NEJM, 2015
96. CheckMate 204 Study Design
Presented By Hussein Tawbi at 2019 ASCO Annual Meeting
98. Intracranial Tumor Burden Change and Characteristics of Intracranial Response – Asymptomatic Patients
Presented By Hussein Tawbi at 2019 ASCO Annual Meeting
99. CM 214: Nivolumab plus Ipilimumab versus Sunitinib
in Advanced Renal-Cell Carcinoma
Motzer R, NEJM, 2018
1096 patients were assigned
to receive nivolumab plus
ipilimumab or sunitinib
100. Survival
Time
Modified from Ribas A, et al. Clin Cancer Res. 2012;18:336-341.
Survival Pattern with Chemotherapy, ICI and IO-IO
ICI
Chemotherapy
ICI: Immune checkpoint inhibitor
IO-IO: Combination ICIs
IO-IO
103. Gastroesophageal cancer
Breast cancer (TNBC)
Hodgkin’s lymphomaMerkel-cell carcinoma
Microsatellite-instability
(tumor agnostic)
SCLC
NHL
ThyroidHCC
104. Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA
Medellín
Inspirado en: Michael Bierut, 2013, Logo para Mohawk Fine Papers
@Onconerd