4. • Increased risk of cancer in immunosuppressed
• Increased risk of certain cancers with the use of
immunosuppressing agents
• Longer OS when Tumor-Infiltrating Lymphocytes present
8. 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
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
26. 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
27. 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
28. 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.”
34. 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”
37. 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
38. 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
39. 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
40. 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
41. 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
50. 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
68. CD3+ T-Cells
Metallic beads covered with Anti CD3 / Anti CD28
Vairy S, Drug Des Devel Ther, 2018
Anti CD3 / Anti CD28
69. CD3+ T-Cells
Metallic beads covered with Anti CD3 / Anti CD28
CD3+ T-Cells
CD3+ T-Cells
Vairy S, Drug Des Devel Ther, 2018
Anti CD3
Anti CD137 (agonist)
70. CD3+ T-Cells
Metallic beads covered with Anti CD3 / Anti CD28
CD3+ T-Cells
CD3+ T-Cells
Selective expansion and
priming of CD3+ T-Cells
Vairy S, Drug Des Devel Ther, 2018
72. Tisagenlecleucel
CTL019
CD3ζ
CD-137
CD8-α hinge region
anti-CD19 scFv
Extracellular
Intracellular
Vairy S, Drug Des Devel Ther, 2018
Antigen
recognition (CD19)
Better
CD19-anti CD19
interactions (steric)
Better cytokine production
and proliferation, and
enhances persistence of
CAR-T cells
76. CAR T-Cell
Vairy S, Drug Des Devel Ther, 2018
Characteristics
Highly activated T-Cell
Ability to seek and
destroy CD19+ cells
(B-Cell leukemia or
DLBCL)