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Slide 1
Immunotherapy in Lung CancerLyudmila Bazhenova, MD
Associate Clinical Professor,
Moores UCSD Cancer Center
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Slide 2
Disclosures
• No disclosures relevant to this talk
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Slide 3
Objectives
• Review immune pathways
▫ Immunology 101
• Review pitfalls of immunotherapeutic agents
▫ irRC
▫ Flair phenomenon.
• Review several agents in development
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Slide 4
Evolution of L. Bazhenova, MD
V 1.0
2002
• Chemotherapist
• Vocabulary: NSCLC
• Visual aid:
V 2.0
2008
• Histopathologist
• Vocabulary: CK 7, CK 20, TTF-1, CK 5/6, p63
• Visual aid:
V3.0
2010
• Molecular biologist
• Vocabulary: EGFR, KRAS, ALK, BRAF, C-MET, PI3K, HER2, MAPK 21, MEK, AKT, FISH, PCR…..
• Visual aid:
V 4.0
In the works
• Budding Immunologist
• Vocabulary: THL, CTLA4, MHC, B7, Antigen, TGF, IL-2
• Visual aid:
100%
NSCLC
60%
30%
5% 5%
adenocarcinoma SCC Large cell carcinoma NOS
KRAS, 30%
EGFR, 15%
EML4-ALK, 5%HER 2, 2%BRAF, 2%
FGFR4, 2%
PIK3CA, 1%
MEK, 1%
Unkn, 42%
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Slide 5
Current state of the art
• Several immunotherapy agents are now in phase III trials
▫ 1 just completed its accrual, another one is expected to finish in 6 months
• Increased interest after approval of sipuleucel-T and ipilimumab
• Patients LOVE this studies.
▫ No problems completing accrual
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Slide 6
Immunotherapeutic strategies
• Non specific immune stimulants
▫ Talactoferrin
▫ Toll like receptor agonists
Cadi-05 (TRL2 agonist)
▫ Anti CTL4 antibodies.
Ipilimumab
• Monoclonal antibodies to tumor antigens
• Vaccines
▫ Dendritic cell vaccines
▫ Tumor cell vaccines
GM-CSF modified tumor cell vaccine
Belagenpumatucel-L
▫ Protein/peptide vaccines
IDM -2101
MAGE A3 vaccine
L-BLP25
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Slide 7
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Slide 8
[TITLE]
Slide courtesy of Raffit Hassan. MD
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Slide 9
[TITLE]
Slide courtesy of Raffit Hassan. MD
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Slide 10
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Slide 11
Nov 2009
Feb 17 2010
Started on Phase III Belagenpumatucel-L trial December 2009
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Slide 12 Tissue biopsy
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Slide 13 Pseudoprogression
Nov 2009
Feb 17 2010
Mar 12 2010
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Slide 14 Paradigm shift
Traditional chemotherapy-cytotoxic
Targeted therapy-cytostatic for unselected patients
Immune therapy-continuum of biological events
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Slide 15 Continuum of biological events
Immune activation and T-cell proliferation Early
Clinically measurable antitumor effects mediated by activated immune cells
Weeks to months
Potential delayed effect on survival
Months to years
Hoos, JNCI, vol 102, Sep 2010
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Slide 16 Measuring response –a holy grail of
clinical trials
• WHO, RECIST, RECIST 1.1 assume that decrease in the tumor size is an evidence of activity of anticancer agent.
• Immunotherapy agents do not obey those rules.
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Slide 17 Response patterns in melanoma patients treated
with anti CTLA-4 antibody ipilimumab
Wolchok, Clin CancerRes 2009; 15
Immediate response “Stable disease” with slow, steady decline in total tumor burden
Response after initial progression Initial mixed response
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Slide 18 Resected progressing metastatic melanoma
lesion in a patient treated with ipilimumab
Wolchok, Clin CancerRes 2009; 15
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Slide 19 Cancer Vaccine Clinical Trial Working
Group (CVCTWG)
Appearance of measurable clinical activity may take longer for immunotherapeutics
Responses can occur after conventional RECIST defined progression
Discontinuation of vaccine therapy might not be appropriate for some progressive patients unless the progression is confirmed.
Durable stable disease may represent clinical benefit
Hoss, J Immunother, 2007, vol 30
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Slide 20
Index lesion New measurable lesion Total sum
Immune related response criteria
(irRC)Tumor burden=SPDindex lesions + SPDnew measurable lesions
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Slide 21 mWHO vs. irRC
CR PR SD PD
mWHOCriteria
All lesions gone
SPD of index lesions
decreases ≥50%
SPD of index lesions of
neither CR, PR or PD
SPD of indexlesions
increases ≥25% and/ornew lesions
developNew lesions not allowed
irCR irPR irSD irPD
irResponse criteria
All lesions gone
SPD of index and any new
lesions decreases
≥50%
New lesions are allowed
SPD of index and any new
lesions neither irCR, irPR or irPD
New lesions allowed
SPD of index and any new
lesions increase
≥25%
Wolchok, Clin CancerRes 2009; 15
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Slide 22 Summary of irRC
• Appearance of new lesions no longer automatically signifies progression as in WHO. ▫ unless they add to a tumor burden by at least 25%
• If patient is classified as irPD confirmation of progression is required. ▫ Confirmation is done at the discretion of investigator in the context
of tumor type, patient overall clinical status
• The new response patterns appear to be clinically meaningful as they correlate with improved outcomes.
• Further confirmation of irRC is needed in the prospective clinical trials▫ They are not ready for wide acceptance
▫ AND they are not accepted by FDA on immune studies.
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Slide 23
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Slide 24
Ipilimumab (Ipi)
• Fully human monoclonal anti CTLA4 antibody▫ CTLA4 inhibits anti-tumor immunity.
▫ Blocking CTLA4 potentiates T cells
• Improves survival in metastatic melanoma
• Serious, potentially life threatening immune toxicities
▫ Colitis, dermatitis, hepatitis, neuritis.
▫ Early diagnosis and prompt treatment of those management is required.
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Slide 25
[TITLE]
Slide courtesy of Raffit Hassan. MD
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Slide 26
Study design
• Objectives:▫ To evaluate safety and efficacy of ipilimumab in combination with
chemotherapy
▫ Primary endpoint irPFS
▫ Evaluate 2 different schedules Tumor antigen present before Ipi started (aka give chemotherapy first
for 2 cycles)
Ipi started at the same time as chemotherapy.
• Key inclusion criteria▫ Chemotherapy naïve patients with ECOG 0-1 without brain
metastases or autoimmune disease
• Response evaluated by both WHO and irRC
Lynch et al, abs #7531 ASCO 2011
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Slide 27 Trial CA184-041 Study Design
Arm AIPI + ChemoConcurrent
Arm BIPI + Chemo
Phased*
Arm CChemo only
Placebo
Treatment Phase Maintenance Phase
Follow-
up
phase
C C C C C C
C C C C C C
C C C C C C
p p
p p p p p p
IPI IPI
IPI IPI
p p
q3w q12w
Follow-
up
phase
Follow-
up
phase
Chemo: Paclitaxel (175 mg/m2)/Carboplatin (AUC=6) IV
C: chemotherapy doublet
IPI: Ipilimumab (10 mg IV)
p: Placebo
p p IPI IPI IPI IPI
IPI IPI IPI IPI
R
A
N
D
O
M
I
Z
E
1:1:1
n=204
(N=203)
Note: Steroids were given as premedication. * The term ‘sequential’, which was listed in the abstract, is now referred to
as ‘phased’ to more accurately reflect the schedule.
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Slide 28 Kaplan-Meier Plots of irPFS per irRC
Concurrent Schedule
Phased Schedule
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Slide 29 Kaplan-Meier Plot of Interim Overall Survival
Concurrent Schedule
Phased Schedule
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Slide 30
Results
Concurrent Phased Placebo
ir BORR 21% 32% 18%
irDCR 70% 86.8% 81.8%
irPFS 5.5m
HR 0.775P= 0.094
5.7m
HR 0.69P=0.026
4.6m
OS 11m
HR 0.962P=0.429
11.6m
HR 0.748P=0.104
10m
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Slide 31 Key Immune-Related Adverse Events
• No grade 4 dermatologic or gastrointestinal irAEs were observed
• Fatal (grade 5) toxic epidermal necrolysis (TEN) was observed in 1 patient in Arm A
• Hypopituitarism and adrenal Insufficiency were not observed
• 2 patients experienced grade 1-2 hypothyroidism (1 each in Arm A and B, respectively)
Arm A
Concurrent
IPI + Chemo
(N=71)
Arm B
Phased
IPI + Chemo
(N=67)
Arm C
Placebo
Chemo Only
(N=65)
N(%)
Total Gr 3 Gr 4 Total Gr 3 Gr 4 Total Gr 3 Gr 4
Any irAE 46 (64.8) 13 (18.3) 1 (1.4) 44 (65.7) 7 (10.4) 3 (4.5) 34 (52.3) 4 (6.2) 0
Dermatologic 40 (56.3) 3 (4.2) 0 35 (52.2) 2 (3.0) 0 31 (47.7) 1 (1.5) 0
Pruritus 12 (16.9) 0 0 5 (7.5) 0 0 4 (6.2) 1 (1.5) 0
Rash 20 (28.2) 2 (2.8) 0 9 (13.4) 2 (3.0) 0 6 (9.2) 1 (1.5) 0
Gastrointestinal 21 (29.6) 5 (7.0) 0 16 (23.9) 4 (6.0) 0 11 (16.9) 2 (3.1) 0
Diarrhea 21 (29.6) 5 (7.0) 0 15 (22.4) 3 (4.5) 0 10 (15.4) 2 (3.1) 0
Colitis 0 0 0 2 (3.0) 2 (3.0) 0 0 0 0
AST* 4 (5.6) 2 (2.8) 0 4 .(6.0) 0 0 2 (3.1) 0 0
ALT* 4 (5.6) 2 (2.8) 0 5 (7.5) 1 (1.5) 0 2 (3.1) 0 0
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Slide 32
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Slide 33
Cancer Vaccines
Cell Based
Dendritic cells Tumor cells
Antigen/peptide based
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Slide 34
Vaccines
• Dendritic cell vaccines
• Tumor cell vaccines
▫ GM-CSF modified tumor cell vaccines
▫ Belagenpumatucel-L
• Protein/peptide vaccines
▫ IDM-2101
▫ MAGE A3 vaccine
▫ L-BLP25
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Slide 35
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Slide 36
Belagenpumatucel-L
Belagenpumatucel-L is a nonviral therapeutic vaccine comprised of 4 TGF-β2 antisense gene-modified allogeneic NSCLC cell lines.
2 adenocarcinoma, 1 Squamous cell carcinoma, 1 large cell carcinoma.
TGF-β2 production is blocked
Irradiated and cryopreserved
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Slide 37
1:1:1
Cohort 1
1.25x107
Cells/injection
Cohort 2
2.5x107
Cells/injection
Cohort 3
5 x 107
Cells/injection
Phase II study design
Key inclusion criteria:• Histologically confirmed NSCLC • PS ≤2, • stages II-IV (AJCC 6.0) • tumor burden of < 125mL
Stage breakdown:2 stage II12 stage IIIA14 stage IIIB47 stage IV
Intradermal injections administered monthly at 3 clinical sites.
Nemunaitis J et al. JCO 2006
R
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Slide 38 Safety and Tolerability of
Belagenpumatucel-L
• Adverse events:
▫ Injection site reactions
▫ Flu-like symptoms
• All are transient
• All are ≤ grade 2
Slide courtesy of Dan Shawler, PhD
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Slide 39
Overall Survival by Cohort, All Patients
N = 75
Survival Cohort
NMedian
(months) 1-yr 2-yr 5-yr 7-yr1 25 10.4 42% 21% 17% 20%2 26 21.8 67% 46% 21% 9%3 24 15.8 57% 39% 22% 23%
Cohort 1Cohort 2Cohort 3
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Slide 40 Overall Survival by Cohort, Stage
IIIB/IV
N = 61
Cohort 1Cohort 2Cohort 3
SurvivalCohort
NMedian
(months) 1-yr 2-yr 5-yr 7-yr1 20 6.9 45% 20% 20% 20%2 20 14.9 60% 40% 17% 7%3 20 15.9 62% 43% 20% 22%
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Slide 41
Overall Survival
N = 29
NMedian
(months) 1-yr 2-yr 5-yr 7-yrSD, PR, or CR 18 44 65% 59% 50% 50%
PD 11 14 64% 36% 14% 0%
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Slide 42
1:1
Arm A
2.5x107
Cells/injection
+BSC
Arm B
Placebo
+BSC
STOP trial Phase III. Double blind. N=506Started: October 2008Expected completion June 2012
Key inclusion criteria:• Histologically confirmed NSCLC
• IIIA (T3N2)• IIIB• IV
• Maintenance therapy for patients with SD or better following frontline chemotherapy
Primary Objective Overall Survival
Secondary Objectives:Adverse eventsTumor progressionQuality of life
R
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Slide 43
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Slide 44
L-BLP 25
• MUC 1 (mucin1) –glycoprotein antigen
▫ Commonly overexpressed in lung cancer and aberrantly glycosylated.
• L-BLP 25 is a liposomal vaccine containing peptides of the extracellular domain of MUC1 + adjuvant.
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Slide 45
1:1
Arm A
L-BLP25*
Arm B
BSC
Phase IIB study design
N=171Key inclusion criteria:• Histologically confirmed NSCLC • Stage IIIB or IV• Maintenance therapy for patients
with SD or better following frontline chemotherapy
Stage breakdown:IIIB Locoregional N=65IIIB MPE/IV N=106
Injections intradermal, weekly x 8 weeks, followed by q6 weeks till progression
* Patients randomized to vaccine arm received cyclophosphamide 300mg/m2 3 days before vaccine injection
R
C. Butts, J Cancer Res Clin Onc, epub
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Slide 46
Safety
• Well tolerated.
• Most common side effects attributable to vaccine
▫ Flu like symptoms
▫ Injection site reactions
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Slide 47
Su
rviv
al
dis
trib
uti
on
fu
nct
ion
Survival time (months)
1.00
70
0.75
0.50
0.25
0.00
0 10 20 30 40 50 60
HR = 0.745, 95% CI 0.533, 1.042
L-BLP25 (n=88)
BSC (n=83)
Censored observation
Slide courtesy of Charles Butts
Cohort
NMedian
(months) 3yrBLP25 88 17.2 31%
BSC 83 13.0 17%p 0.035
Overall survival, all patients.
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Slide 48
Su
rviv
al
dis
trib
uti
on
fu
nct
ion
Survival time (months)
1.00
70
0.75
0.50
0.25
0.00
0 10 20 30 40 50 60
HR = 0.878, 95% CI 0.587, 1.313
L-BLP25 (n=53)
BSC (n=53)
Censored observation
Cohort
NMedian
(months) 3yrBLP25 53 15.1 19%
BSC 53 12.9 11%p 0.278
Overall survival, IIIB (effusion), IV
Slide courtesy of Charles Butts
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Slide 49
Su
rviv
al
dis
trib
uti
on
fu
nct
ion
Survival time (months)
1.00
70
0.75
0.50
0.25
0.00
0 10 20 30 40 50 60
HR = 0.548, 95% CI 0.301, 0.999
L-BLP25 (n=35)
BSC (n=30)
Censored observation
Cohort
NMedian
(months) 3yrBLP25 35 30.6 49%
BSC 30 13.3 27%p 0.07
Overall survival, IIIB
Slide courtesy of Charles Butts
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Slide 50
1:1
Arm A
L-BLP 25
+BSC*
Arm B
Placebo
+BSC
START trial Phase III. Double blind. N=1500• Started: December 2006• Completed accrual.
Key inclusion criteria:• Histologically confirmed NSCLC
• Unresectable IIIB • Maintenance therapy following
curative chemoXRT
Primary Objective Overall Survival
Secondary Objectives:TTSFTTPAdverse events
* Patients randomized to vaccine arm received cyclophosphamide 300mg/m2 3 days before vaccine injection
R
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Slide 51
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Slide 52
MAGE-A3 Vaccine
• MAGE –melanoma associated antigen
▫ Expressed in 35-40% of lung cancers
▫ Expression increases with stage and associated with poor prognosis
• MAGE A3 is a recombinant protein vaccine combined with proprietary immunological adjuvant ASO2B
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Slide 53
R 2:1
Arm A
MAGE A3
vaccine
+BSC
Arm B
BSC
Phase II MAGE A3 study design
Key inclusion criteriaTumor expresses MAGE AgStages IB-II surgically resected
1089 surgical specimens evaluated363 positive for MAGE182 entered the trial
IB 123IIA 8IIB 35IIIA 16
IM q 3 weeks x 5, followed q3m x 8
Primary endpoint DFI
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Slide 54
Safety
• Well tolerated
▫ Grade 1 and 2 local or systemic reactions
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Slide 55
Vansteenkiste. ASCO. 2007 (abstr 7554)).
27% reduction in relative risk of cancer
recurrence following surgery
Randomized Phase II Trial of MAGE-A3
Vaccine in MAGE-A3+ NSCLC
Time From Surgery (Months)
DFS
HR=0.73 P=0.093
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
DF
S D
istr
ibu
tio
n
0 6 12 18 24 30 36 42 48 54
MAGE-A3
Placebo
DFI
Time From Surgery (Months)
HR=0.73 P=0.107
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0D
FS
Dis
trib
uti
on
0 6 12 18 24 30 36 42 48 54
MAGE-A3
Placebo
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Slide 56
R 2:1
Arm A
MAGE A3
vaccine
+BSC
Arm B
BSC
MAGRITPhase III double blind. N=2270Started October 2007Estimated completion December 2022
Key inclusion criteriaTumor expresses MAGE AgStages I-III surgically resectedStratified by adjuvant therapy
received or not
Primary objectives Disease free survival
Secondary objectiveProspective validation of a
predictive gene signatureStage IB of BSC closedStage IIIA of chemotherapy closed
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Slide 57
What have we learned over the years
• Developing immunotherapies is not the same as developing cytotoxics▫ Responses take longer▫ “resist RECIST”
• Lower bulk tumors could derive more benefit• Generally not toxic• Stay tuned for results of phase III trials
▫ MAGRIT Resected I-III
▫ START and INSPIRE unresectable treated IIIB (locoregional)
▫ STOP Treated advanced IIIA Unresectable treated IIIB Controlled IV
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Slide 58
Immunotherapy agents that I did not
cover.• GVAX
▫ An adenoviral gene-based autologous vaccine
• TG4010.05
▫ Vaccinia virus coding for MUC1 and IL2
• IDM 2101
• Talactoferrin
• Cadi-05
▫ (TRL2 agonist)
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Slide 59
Evolution of L. Bazhenova, MD
V 1.0
• Chemotherapist• Vocabulary: NSCLC• Visual aid:
V 2.0
• Histopathologist• Vocabulary: CK 7, CK 20, TTF-1, CK 5/6, p63• Visual aid:
V3.0
• Molecular biologist• Vocabulary: EGFR, KRAS, ALK, BRAF, C-MET, PI3K, HER2, MAPK 21, MEK, AKT, FISH, PCR…..• Visual aid:
V 4.0
• Budding Immunologist• Vocabulary: THL, CTLA4, MHC, B7, Antigen, TGF, IL-2• Visual aid:
V 5.0• ????????
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