Immune checkpoint inhibitors in thoracic malignancies
Rolf Stahel University Hospital Zürich Switzerland
Zürich 18.11.2015
ETOP | Name Project | Title Presentation | Zurich, July 27, 2009
Immune checkpoint inhibitors in thoracic malignancies
• Advanced NSCLC • Activity in pretreated patients • PD-L1 and other potential biomarkers • Activity in first line
• Earlier stages NSCLC • Consolidation after chemoradiotherapy • Adjuvant after section
• Small cell lung cancer • Mesotheliioma • Thymic carcinoma
2
Evolution of second line therapy for NSCLC: Key studies
3
Shepherd, JCO 2000
Docetaxel > BSC
Non-inferiority of pemetrexed to docetaxel
Hanna, JCO 2004
Erlotinib > placebo (2nd or 3rd line)
Shepherd, NEJM 2005
Docetaxel plus nintedanib (LUME-Lung-1) or docetaxel plus ramucirumab (REVEL) versus docetaxel plus placebo for second-line treatment of stage IV NSCLC: Overall survival benefit
4
LUME-Lung 1: Adenocarcinoma
OS 12.6 vs 10.3 ms OS 10.5 vs 9.1 ms
Reck, Lancet Oncol 2014; Garon, Lancet Oncol 2014
REVEL: 25% squamous cell carcinoma
Activity of immune checkpoint inhibitors in pretreated patients with advanced NSCLC
5
Nivolumab Pembrolizumab
Atezolizumab Durvalumab Avelumab
N 129 475 175 228 184RR
SCC Non-SCC
17% 18%
23.5% 19%
27% 21%
21% 13%
14%
Drug rel AE All grades Grade 3/4
41% 4.7%
71% 9.5%
66% 11%
50% 8%
77% 12%
RR PDL-1 + PDL-1 -
16% 13%
42% (>50%) 10% (<1%)
34% IC2/3 or TC 2/3
Gettinger S, J Clin Oncol 2015; 33: 2004-2012; Herbst R, Nature 2014; 515: 563-7; Soria JC, ESMO 2013; Garon E, NEJM 2015; 372: 2018-28;
Rizvi N, ASCO 2015; Guley LJ, ASCO 2015
Monotherapy with anti-PD1 nivolumab in second or later line NSCLC (phase I data)
6
Pts at Risk
Group Died/TreatedMedian OS, mo (95% CI) 1-year 2-year 3-year
9.2 (5.3, 11.1) 14.9 (7.3, 30.3) 9.2 (5.2, 12.4)
Months Since Initiation of Treatment
10090807060
0
5040302010
0 3 6 9 12 15 18 30 33272421 36 39 42 45 48 51 54 66636057
Censored
3-year OS = 27%2-year OS = 42%
Nivolumab 1 mg/kgNivolumab 3 mg/kgNivolumab 10 mg/kg
OS
(%)
33 (17, 49) 56 (38, 71) 38 (26, 50)
15 (5, 30) 42 (24, 58) 20 (11, 31)
15 (5, 30) 27 (12, 43) 14 (7, 25)
26/33 23/37 50/59
1 mg/kg 3 mg/kg 10 mg/kg
33 37 59
26 34 51
21 26 35
16 21 29
9 17 22
7 14 16
6 13 14
6 12 12
4 11 11
4 9 10
4 9 9
3 7 9
1 5 6
1 2 4
0 1 2
0 1 2
0 1 2
0 1 1
0 1 1
0 1 0
0 1 0
0 1 0
0 0 0
OS rate, % (95% CI)
Gettinger, Chicago 2014
• 54% pretreated with 3-5 therapies • 17% confirmed responses, 5% unconventional iR
Monotherapy with anti-PD1 pembrolizumab in second or later lane (phase 1 data)
7
• Pretreated pts. Same efficacy 2mg or 10mg/kg • Lower ORR in patients with liver metastases: 13.6% vs 21.2%
Hellman, WCLC 2015
Randomized phase II study comparing atezolizumab (vs docetaxel in 2L/3L NSCLC (POPLAR)
8
Vansteenkiste, ECCO-ESMO 2015
Median 12.6 mo (9.7, 16.4)
Median 9.7 mo (8.6, 12.0)
Minimum follow up = 13 months
HRa = 0.73 (0.53, 0.99) P value = 0.040
AtezolizumabDocetaxelCensored+
POPLAR: OS by PD-L1 Expression
0,1 1 10
In favor of docetaxel
0.73
1.04
0.59
0.54
0.49
Hazard Ratioa
In favor of atezolizumab
47 (16%)
105 (37%)
198 (68%)
92 (32%)
N = 287
0.2 1 2
Median OS (95% CI), moDocetaxel n = 143
7.4 (6.0, 12.5)
9.7 (8.6, 12.0)
9.7 (8.6, 12.0)
9.2 (7.3, 12.8)
11.1 (6.7, 14.4)
Atezolizumab n = 144
15.1 (8.4, NE)
12.6 (9.7, 16.4)
9.7 (6.7, 12.0)
15.5 (11.0, NE)
15.5 (9.8, NE)
n (%)
TC3 or IC3
TC2/3 or IC2/3
TC1/2/3 or IC1/2/3
TC0 and IC0
Subgroup
ITT
Vansteenkiste, ECCO-ESMO 2015
Effect of second line nivolumab on lung term surival: Confirmation of CheckMate 63
10
CheckMate 63:all histologies, 56% > 3rd line: 18-months OS rate 27%
CheckMate 17:SCC, 2nd line: 18-months OS rate 28%
CheckMate 57: Non-SCC, 2nd line: 18-months OS rate 38%
Horn, WCLC 2015
Second line therapy of squamous cell lung cancer: Comparisons accross recent studies
Nivolumab vs Doc:9.2 vs 6.0 months; HR 0.62 (0-48-0.81)
Pemetrexed vs Doc6.2 vs 7.4 months; HR 1.56 (0.8-2.26)
Docetaxel Ramucirumab vs Doc9.5 vs 8.2 months; HR 0.88 (0·69–1.13)
Docetaxel Nintedanib vs Doc8.6 vs 8.7 months; HR 1.01 (0.85-1.21)
Afatinib vs Erlotinib7.9 vs 6.8 months; HR 0.81 (0.69-0-95)
11
Reck, ECC0-ESMO 2015: Scaglotti Clin Lung Cancer 2010; Garon, Lancet Oncol 2014; Reck, Lancet Oncology 2014; Soria, Lancet Oncol 2015
Second line therapy of non-squamous cell lung cancer: Comparisons accross recent studies
Nivolumab vs Doc:12.2 vs 9.4 months; HR 0.73 (0-59-0.89)
Pemetrexed vs Doc9.3 vs 8.0 months; HR 0.78 (0.61-1.00)
Docetaxel Ramucirumab vs Doc11.1 vs 9.7 months; HR 0.83 (0.71–0.97)
Docetaxel Nintedanib vs Doc12.6 vs 10.3 months, HR 0.83 (0.7-0.99)
12
Horn, ECC0-ESMO 2015: Scaglotti Clin Lung Cancer 2010; Garon, Lancet Oncol 2014; Reck, Lancet Oncology 2014
Treatment effect on overall survival in predefined subsets 13
Borghaei. NEJM 2015
Phase III study of nivolumab versus docetaxel in second line non-squamous cell lung cancer (CheckMate-57): Overall survival
14
Nivolumab (n = 292)
Docetaxel (n = 290)
mOS, mo 12.2 9.4
HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015
Nivolumab
Docetaxel
1-yr OS rate = 51%
1-yr OS rate = 39%
292 232 194 169 146 123 62 32 09
290 244 194 150 111 88 34 10 05
Nivolumab
Docetaxel
Number of Patients at Risk
OS
(%)
Time (months)
100
90
80
70
60
50
40
30
10
0
20
27211815129630 24
Paz-Ares, ASCO 2015;
PD-L1 expression15
CheckMate 17 CheckMate 57 KEYNOTE 1
Pembrolizumab for the treatment of NSCLC: Prevalance of PD-L1 positivity and response according to PD-L1 positivity
16
Garon, AACR 2015
PD-L1 as a biomarker
PD-L1 IHC score
0
3
5
8
10
0 10 20 30 40 50 60 70 80 90 100
‘Negative’ ‘Positive’
Response?
Differential effects depend upon the Dose-response relationship
Courtesy Keith Kerr
Mutational landscape determines sensitivity of PD-1 blockade in NSCLC: Candidate neoantigens, response and PFS
18
Rizvi, Science 2015
15LBA: High tumoral IFNγ mRNA, PD-L1 protein, and combined IFNγ mRNA/PD-L1 protein expression associates with response to durvalumab (anti-PD-L1) monotherapy in NSCLC patients – Higgs B et al
• Key results – The ORR was 16% [32/300] (95%CI 11, 22) and pre-treatment PD-L1 status influenced
response: patients who were PD-L1 positive had an ORR of 27% [23/84] (95%CI 18, 38) compared with 5% [5/92] (95%CI 2, 12) for patients who were PD-L1 negative
– ORR by PD-L1 and IFNγ status is shown in the figure
Higgs et al. Ann Oncol 2015; 26 (suppl 6): abstr 15LBA
OR
R (%
)
0
25
50
75
100
31311
46
3327
PD-L1 +ve -ve +ve -ve +ve -ve
IFNγ -ve +ve +ve +ve -ve -ve
Prevalence 37% 35% 18% 19% 22% 41%
Less toxicity with immune checkpoint inhibitors in comparative studies
20
Toxicity Nivolumab squamous %
Docetaxel squamous %
Afatinib squamous %
Docetaxel / Ramucirumab %
All 59 87 93 98
Grade 3-4 8 58 57 79
Grade 5 0 2 2 5
Peters, WCLC 2015
CheckMate 57: Treatment-related adverse events21
Nivolumab (n = 287) Docetaxel (n = 268)Any Grade, % Grade 3–4,a % Any Grade, % Grade 3–4,a %
Total patients with an event 69 10 88 54Fatigue 16 1 29 5Nausea 12 1 26 1Decreased appetite 10 0 16 1Asthenia 10 <1 18 2Diarrhea 8 1 23 1Peripheral edema 3 0 10 <1Myalgia 2 <1 11 0Anemia 2 <1 20 3Alopecia <1 0 25 0Neutropenia <1 0 31 27Febrile neutropenia 0 0 10 10Leukopenia 0 0 10 8
Treatment-related adverse events reported in≥10% of patients
EQ-5D Utility Index:Mean Scores Over Time While on Treatment
22
Lung Cancer Norm (UK-based): 0.67b
Mea
n EQ
-5D
Util
ity In
dex
Scor
e
97 50 32 32 21 18 13 13 8Nivolumab (n = 97)
88 32 9 5 5 4 4 2 1Docetaxel (n = 89)
0 12 24 30 36 42 48 54 60
1.0
0.9
0.8
0.7
0.6
0.5
0.4
Population Norma
DocetaxelNivolumab
24
Higher scores indicate better health status. Only time points that had PRO data available for ≥5 patients in either treatment arm are plotted on the graph.
Week
Reck, ECCO-ESMO 2015
Pembrolizumab for the treatment of NSCLC: PD-L1 staining of tumor cells
23
Garon, AACR 2015; NEJM 2015
Pembrolizumab first line date (Keynote 001)24
Rizvi, ASCO 2015
Median PFS was6.1 months in all treated patients and 12.5 months with >50% PD-L1 staining
OS was not reached in all treated patients or in patients with ≥50% staining, and was 16.2 months and 10.4 months in patients with staining in 1%–49% and <1% of cells, respectively
BIRCH: Atezolizumab in TC2/3 and/or IC2/3 NSCLC25
0
10
20
30
3L+ 2L 1L
27%24%
26%
17% 17%19%
TC2/3 or IC2/3TC3 or IC3
OR
R, %
n = 65n = 139n = 267n = 253 n = 115 n = 122
• BIRCH met its primary endpoint in all predefined subgroups per protocol-specified criteria • Majority of responses were ongoing (> 61% in TC3 or IC3) • Median DOR was 7 mo in 3L+, NR in 1L/2L in TC3 or IC3, although follow-up is limited • IRF- and INV-assessed ORRs (per RECIST v1.1) were similar. In TC3 or IC3, eg, 27% vs 29% in
3L+; 24% vs 25% in 2L; and 26% vs 31% in 1L, respectivelyBesse, ECCO-ESMO 2015
Chemotherapy combination trials26
GP28328PhIb solid tumours (incl.
1L NSCLC) atezo + chemo (n=58)
KEYNOTE-021 PhI/II 1L NSCLC pembro + chemo
(n=49)
CheckMate 012PhI 1L NSCLC
nivo (N) + chemo (n=56)
CheckMate 012PhI 1L NSCLC nivo (N) + ipi (I)
(n=49)
Atezo + carbo/pac
Atezo + carbo/pem
Atezo + carbo/abrax
Pembro + carbo/pac
Pembro + carbo/pem
N10 + gem/cis
N10 + pem/cis
N10 + carbo/pac
N5 + carbo/pac
N1 q3w +I1 q3w
N1 q2w +I1 q6w
N3 q2w +
I1 q12w
N3 q2w +I1 q6w
n 8* 17* 16* 25 24 12 15 15 15 31 40 38 39
ORR, %
Grade 3–4 treatment-related AEs
69% 35% 45%
71% 54% 85% 32% 38% 25% 47% 73% 29% 29% 35% 29% 28%
0
25
50
75
100
50
77
56
28
58
3347 47 43
1325
39 31
Refs.
Camidge, et al.WCLC 2015
Giaccone, et al. ECC 2015
Papadimitrakopoulos, et al. ASCO 2015
Gettinger, et al. ESMO 2014
Rizvi, et al.WCLC 2015
Immunotherapy combination trial: CheckMate-12 ipilimumab and nivolumab. Treatment-related AEs
27
• There were no treatment-related deaths. Toxicities mailnly GI, hepatic, endocrine, skin, lung
Nivo 1 + Ipi 1 Q3W
(n = 31)
Nivo 1 Q2W + Ipi 1 Q6W
(n = 40)
Nivo 3 Q2W + Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W + Ipi 1 Q6W
(n = 39)Nivo 3 Q2Wa
(n = 52)
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Treatment-related AEs, % 77 29 73 35 74 29 69 28 71 19
Treatment-related AEs leading to discontinuation, % 13 10b 8 8c 5 3d 10 10e 10 10f
Nivolumab Median number of doses(range) Median duration of therapy, wks (range)
4(1–42) 12.0
(3.0–92.0)
7(1–26) 16.0
(2.0–59.0)
13(1–26) 28.7
(2.0–52.0)
8(1–25) 18.0
(2.0–53.0)
8(1–62) 16.0
(2.0–129.6)
Ipilimumab Median number of doses(range) Median duration of therapy, wks (range)
NC 1–4g
11.6(3.0–24.0)
3(1–9) 17.6
(6.0–59.0)
3(1–5) 35.7
(12.0–60.0)
2(1–9) 15.0
(6.0–54.0)
NA
NA
Immunotherapy combination trial: CheckMate-12 ipilimumab and nivolumab: Efficacy by PD-L1 expression
28
≥1% PD-L1 expression <1% PD-L1 expression
Nivo 1+ Ipi 1 Q3W
(n = 12)
Nivo 1 Q2W + Ipi 1 Q6W
(n = 21)
Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 21)
Nivo 3 Q2W + Ipi 1 Q6W
(n = 23)
Nivo 1+ Ipi 1 Q3W
(n = 13)
Nivo 1 Q2W
+ Ipi 1 Q6W
(n = 7)
Nivo 3 Q2W + Ipi 1 Q12W (n = 9)
Nivo 3 Q2W + Ipi 1 Q6W
(n = 7)
ORR, % 8 24 48 48 15 14 22 0
mPFS, wks (95% CI)
11.5 (7.1, )
21.1 (11.4, )
34.6 (15.9, 35.3)
NR (15.4, )
34.0 (8.9, )
NR (10.1, )
23.1 (4.0, )
10.3 (7.4, 12.7)
PFS rate at 24 wks, % (95% CI)
42 (15, 67)
40 (18, 61)
74 (48, 88)
65 (42, 81)
57 (25, 80)
NC 39 (9, 69)
0
• All patients had available pretreatment tumor samples; 76% (113/148) had samples evaluable for PD-L1 expression • Median DOR was not reached in any arm, regardless of PD-L1 expression
Phase 3 anti PD1/PD-L1 Combination Trials in First-Line Advanced NSCLC
Durvalumab MYSTIC
Atezolizumab Impower 110
Ant
i-PD
-1/P
D-L
1
Nivolumab CHECKMATE 227
Primary endpoints: OS, PFS
Nivolumab
Nivolumab + ipilimumab
Platinum-based chemotherapy
Treatment-naïve or recurrent NSCLCN=1980
Atezolizumab
Gemcitabine + cisplatin or carboplatin
Primary endpoint: PFS
Stage IV squamous PD-L1+ NSCLC N=400
Atezolizumab + carboplatin + paclitaxel
Bevacizumab + paclitaxel + carboplatin
Primary endpoint: PFSAtezolizumab + bevacizumab + paclitaxel + carboplatinStage IV non-squamous NSCLC
N=1200
Atezolizumab + carboplatin + nab-paclitaxel
Carboplatin + nab-paclitaxel
Primary endpoint: PFS
Stage IV non-squamous NSCLCN=550
Atezolizumab
Carboplatin or carboplatin + pemetrexed
Primary endpoint: PFSStage IV non-squamous PD-L1+ NSCLC N=400
Atezolizumab + carboplatin + nab-paclitaxel
Carboplatin + nab-paclitaxel
Primary endpoint: PFSAtezolizumab + carboplatin + paclitaxel
Stage IV squamous NSCLCN=1200
Primary endpoint: PFS
Durvalumab
Durvalumab + tremelimumab
SOC chemotherapy
Advanced NSCLC N=675
Durvalumab NEPTUNE
Durvalumab + Tremelimumab
SOC chemotherapy
Primary endpoint: OS
First-line metastatic NSCLC N=800
Atezolizumab Impower 111
Atezolizumab Impower 130
Atezolizumab Impower 131
Atezolizumab Impower 150
Pembrolizumab KEYNOTE-189
Primary endpoints: PFS
Pembrolizumab + pemetrexed/platinum
Pemetrexed/platinum
Treatment-naïve non-squamous NSCLC N=580
Nivolumab CHECKMATE 026
Nivolumab 3 mg/kg IV Q2W
ICCa with potential for crossoverPrimary endpoint:
PFS
Treatment-naïve non-squamous NSCLC PD-L1–positive NSCLC
N=495
Pembrolizumab KEYNOTE-042
Pembrolizumab 200 mg IV Q3W
SOC chemotherapy
Treatment-naïve non-squamous NSCLC PD-L1–positive NSCLC
N=1240
Primary endpoint: OS
Peters, WCLC 2015
Immune checkpoint inhibitors in earlier stages of NSCLC treated with chemoradiotherapy
Consolidation after chemoradiotherapy
• NICOAS: A Feasibility Trial Evaluating Anti-PD1 Nivolumab Consolidation After Standard First-line Chemotherapy and Radiotherapy in Locally Advanced Stage IIIA/B NSCLC
• PACIFIC: A Phase III, Randomised, Double-blind, Placebo-controlled, Multi-centre, International Study of MEDI4736 as Sequential Therapy in Patients with Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy
30
Immune checkpoint inhibitors after complete resection of NSCLC: PEARLS
31
SCLC: Nivolumab and nivolumab – ipiliumab combinations
32
SCLC (n = 128) with progressive disease after ≥1 prior line of therapy, including a platinum-based regimen in first line
(unselected by PD-L1 expression)
Nivolumab 3 mg/kg IV Q2W (n = 40)
Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV Q3W
for 4 cycles (n = 47)
aNivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W
for 4 cycles (n = 38)
Nivolumab 1 mg/kg + Ipilimumab 1 mg/kg IV Q3W
for 4 cycles (n = 3)
Nivolumab 3 mg/kg IV Q2W
Primary objective: ORR per RECIST v1.1 Secondary objective: safety
Exploratory objectives: PFS, OS, biomarker analysis
Database lock: February 16, 2015
Antonia, ASCO 2015
SCLC: Nivolumab and nivolumab – ipiliumab combinations: Tumor responses and PD-L1 expression
33
Antonia, ASCO 2015
150
125
100
75
50
25
0
-25
-50
-75
-100
Bes
t Red
uctio
n fr
om B
asel
ine
in
Ta
rget
Les
ion
(%) <1% PD-L1
≥1% PD-L1Not evaluableb
Confirmed responders
Evaluable samples (40 of 90)
PD-L1 expression level, n (%)<1% ≥1%
Nivolumab (n = 22) 15 (68) 7 (32)Nivolumab + Ipilimumab (n = 18) 12 (67) 6 (33)
150
125
100
75
50
25
0
-25
-50
-75
-100
aCombined data for nivolumab 1 + ipilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts. bNot evaluable due to specimens that are not quantifiable, indeterminate, or not yet obtained; 10 nonevaluable samples and 8 not yet obtained in the nivolumab arm, 6 nonevaluable samples and 26 not yet obtained in the nivolumab 1 + ipilimumab 3 arm. Only pts with target lesion at baseline and ≥1 on-treatment tumor assessment are included (nivolumab, n = 34, nivolumab + ipilimumab, n = 40).
Nivolumab + Ipilimumaba Nivolumab
SCLC: Pembrolizumab34
SCLC: Pembrolizumab (Keynote-28): PD-L1 expression
35
Ott, WCLC 2015
SCLC: Pembrolizumab (Keynote-28): Antitumor activity
36
Ott, WCLC 2015
SCLC: Pembrolizumab (Keynote-28): Change from baseline over time
37
Ott, WCLC 2015
ETOP / IFCT 4-12 STIMULI
STIMULI protocol amendment 138
• Treatment arminduction phase: nivolumab (1mg/kg i.v.) plus ipilimumab (3mg/kg i.v.), Q3W, 4 dosesmaintenance phase: nivolumab (240mg i.v.), Q2W, until PD for max 1 year
• Observation arm: best supportive careChemo-Radiotherapy:
cis-/carboplatin + etoposide 4 cycles
Biomaterial for translational research:
Consolidation vs observation:
induction maintenance
max 1 year
combination nivolumabnivolumab/ipilimumab
observation
Screening:
LD SCLC PCI
Tumourevaluation:
PD
off
Voluntary re-biopsy: → FFPE block
yes
noR
• • •
3 6 9 3 6 9 1812after randomisation
RT (Thoracic Radiotherapy): CT scans for tumour assessmentaccelerated schedule preferred - up to 18 months: every 9 weeksstart: day 1 of chemo cycle 1 or - up to 2 years: every 12 weeks
day 1 of chemo cycle 2 - years 3 & 4: every 6 months- at 5 years
0Week
Serum
At progression:
Whole blood Whole bloodWhole blood
RT
RT
from start of chemotherapy-2
CT
Serum SerumSerum
FDG-PET-CTor CT
Brain MRI or CT
Biopsy: FFPE block
or slides
27 ···
CT • • •
14 16
39
•Pleural plaques
Pleural plaques
Asbestosis
Pleural mesothelioma
Mesothelioma: Pembrolizumab (Keynote-28): PD-L1 screening
40
Alley, WCLC 2015
Mesothelioma: Pembrolizumab (Keynote-28): Antitumor activity
41
Alley, WCLC 2015
Mesothelioma: Pembrolizumab (Keynote-28): Antitumor activirty
42
Alley, WCLC 2015
Intensitiy and duration of therapy?A case of a 70-year old man with stage IV adenocarcinoma of the lung treated with two doses of atezolizumab
43
April 2014: Pretreatment
September 2014: After 2 doses of therapy in June
2014
March 2015: Hilar progression
T cell immune checkpoints as targets for immunotherapy
44
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T Cell Stimulation
BlockingAntibodies
AgonisticAntibodies
InhibitoryReceptors
Activating Receptors
T cell
B7-1
T cell
In Phase 3 Studies
In Phase 1 Development
In Phase 1 Development
● Agonistic antibodies directed towards activating co-stimulatory molecules
● Blocking antibodies against co-inhibitory molecules may enhance T-cell stimulation to promote tumor destruction
45