Table 2

Murine malignancy models: blockade with CTLA-4 (5685). *All days (d) are relative to implantation of tumor cells.

Murine TumorTumor type / Mouse strainAnti-CTLA-4 Ab /Tx regimenResult with CTLA-4 blockade
BrainSMA-560 Glioma/Vm/Dk (56)9H10; d7* (100 μg), d10 (50 μg), d13 (50 μg) post-implantAnti-(CTLA-4 monotherapy = 80% survival; increased CD4+CD25- T cells in lymph nodes/spleen
GL-261 Glioma/C57BL/6 (57)9H10; d0 (100 μg), d3 (50 μg), d6 (50 μg),Anti-CTLA-4 monotherapy = 50% survival
Anti-CTLA-4 + anti-CD25 = 100% survival; massive amount of IFN-γsecreting CD4 and CD8 TIL
OvarianOV-HM/C57BL/6 x C3H/He (58)UC10-4F10-11;1 mg/mouseAnti-CTLA-4 monotherapy = 3/5 tumors rejected [d0, d7, d14)
1/5 rejected (d3, d10, d17); 0/5 rejected (d7, d14, d21), (d14, d21, d28)
BladderMB49/C57BL/6 (59)9D9; d7, d10, d13 (200 μg each)Anti-CTLA-4 monotherapy = tumors rejected
Anti-CTLA-4 + CpG-ODN = improved long-term survival; increased levels Of tumor-reactive T cells and reduced numbers of Tregs at the tumor site
SarcomaMeth-A/BALB/c (60)9H10; d6 (100 μg), d9 (50 μg), d12 (50 μg)Anti-CTLA-4 monotherapy = 20% survival
Anti-CTLA-4 + rMVAp53 = 80% survival
MC38, 11A1 BALB/c, C57BL/6 (61)9H10; d14 (100 μg), d17 (50 μg), d20 (50 μg)Anti-CTLA-4 + MVAp53 + CpG-ODN = 75% survival in both models
BreastTSA/BALB/c (62)9H10; d12, d14, d16 (200 μg each)Anti-CTLA-4 monotherapy = ineffective
Anti-CTLA-4 + IR = 80–90% reduction of tumor volume
4T1 BALB/c (63)9H10; d14, d18, d21 (200 μg each)Anti-CTLA-4 monotherapy = 1/9 mice tumor-free
Anti-CTLA-4 + IR = 6/9 mice tumor-free
4T1 BALB/c (64)9H10; d14, d18, d21 (200 μg each)Anti-CTLA-4 monotherapy = ineffective
Anti-CTLA-4 + IR = tumor rejection/lung metastases inhibition
4T1 BALB/c (65)UC10-4F10-11; d7, d11, d15, d19 (100 μg each)Anti-CTLA-4 monotherapy = ineffective
Anti-CTLA-4 + trimAb = 19/26 mice rejected tumors
SM1/BALB/c (66)9H10; d4, d7, d10 (100 μg each)Anti-CTLA-4 monotherapy = ineffective
Anti-CTLA-4 + SM1/GM-CSF vaccine = 80% of mice rejected tumors
EMT6/BALB/c (67)UC10-4F10-11; d4, d8, d12 (400μg each) Ixa: d3, d7, d11Anti-CTLA-4 monotherapy = 40% of mice showed complete tumor regression
Ixabepilone = 20% of mice showed complete tumor regression
Anti-CTLA-4 + ixabepilone = 100% of mice showed complete tumor regression
ColonMC38/C57BL/6 (68)UC10-4F10-11; d7, d11, d16 (100 μg each)Anti-CTLA-4 monotherapy = ineffective
Anti-CTLA-4 + anti-CD25 + DC vaccine = 90% tumor-tree survival vs. 53% in DC vaccine only; increased CTL in spleen observed with combination
MC38 (69)K4G4, L1B11, L3D10Created human CTLA-4 knock-in mouse – all 3 clones provided increased survival times with differing autoimmune side effect profiles
CT26 BALB/c (70)9H10; d10 (100 μg), d13 (50 μg), d15 (50 μg)Anti-CTLA-4 monotherapy = 45% survival
Anti-CTLA-4 + anti-VEGFR-2 + DC vaccine = 80% survival
Monotherapy tx at d0, d3, d5 = 90% tumor rejection
CT26 BALB/c (67)UC10-4F10-11; d5, d9, d13 (400 μg each) Ixa: d4, d8, d12Anti-CTLA-4 monotherapy = 20% of mice showed complete tumor regression Ixabepilone = ineffective
Anti-CTLA-4 + ixabepilone = 70% of mice showed complete tumor regression
MC38/C57BL/6 (71)UC10-4F10-11; d14, d21, d28 (800 μg each)Anti-CTLA-4 monotherapy = ineffective
Anti-CTLA-4 + anti-4-1BB = >85% of mice rejected tumors
Similar results with tx at d2, d9, d16
LymphomaBW5147.3/AKR (72)UC10-4F10-11; d-1 (250 μg), d0 (250 μg), d4 [100 μg), d8 (100 μg), dl2 (100 μg)Hematopoietic stem cell transplantation + anti-CTLA-4 = anti-leukemic effects
EL4/C57BL/6 (73)9H10; d3, d5 (100 μg each)Anti-CTLA-4 monotherapy = ineffective
Anti-CTLA-4 + DC vaccine = >60% rejected tumors
FibrosarcomaSA1N/A/J (74)9H10; every 4 days (200 μg each)Anti-CTLA-4 monotherapy = significant reduction in tumor burden compared to control IFN-γ neutralization abrogated anti-CTLA-4 therapy
SA1N (67)UC10-4F10-11; d12, d16, d20 (400 μg each) Ixa: d11, d15, d15Anti-CTLA-4 monotherapy = 25% of mice showed complete regression of tumors Ixabepilone = ineffective
Anti-CTLA-4 + ixabepilone = 71.4% of mice showed complete regression of tumors
ProstataTRAMP C1[pTC1]/C57BU6 (75)9H10; d7, d10, d13 (100 μg each)Early passage cells = tumor delay observed
Late passage cells = tumor rejection observed in 5/5 mice
TRAMP C2/C57BL/6 (76)9H10; d4, d7, d10 (100 μg each)Adjunctive monotherapy CTLA-4 therapy post-resection = 60% metastasis-free compared to 0% with control Ab
TRAMP/C57BL (77)9H10; 14–16 week old mice d7, d10, d16 post-tR tx (100 μg each)[Primary adenocarcinoma and metastases develop in transgenic model at 15–20 weeks)
Anti-CTLA-4 + TRAMP C1/C2/GM-CSF vaccine = reduced tumor incidence (15% vs. 75% in control-treated animals)
TRAMP C2/C57BL/6 (78)9H10; d29, d33, d40, d50 (100 μg each) d29=1d post-cryoablationAnti-CTLA-4 monotherapy = ineffective
Cryoablation = ineffective
Anti-CTLA-4 + cryoablation = 45% tumor-free survival; enhanced intratumoral-specific functional CD8+ T cells
MelanomaB16/C57BL/6 (79, 80)9H10; d0, d3, d6 (200 μg each)Enhanced survival with DC vaccine + anti-CTLA-4; greater survival with inclusion of anti-CD25-depleting antibody
B16/C57BL/6 (81)9H10; d6 (100 μg), d8 [50 μg), d10 (50 μg)Anti-CTLA-4 + Trp-2 peptide vaccine + CpG-ODN = delayed tumor growth by 50 days
B16/C57BL/6 (82)9D9; d3, d6, d9Anti-CTLA-4 + Fvax = rejection of 10% of melanomas
Anti-CTLA-4 + Fvax + anti-PD-1 - rejection of 50% of melanomas; increased Teff infiltration
B16/C57BL/6 (83)9H10; d3, d6, d9 (100 μg each)Anti-CTLA-4 + Gvax = 73% long-term survivors;
CTLA-4 blockade on both Teffs and Tregs is synergistic (40% long-term survival if only Teffs blocked)
B16.F10/C57BL/6 (84)9H10; d5 (100 μg), d7 (50 μg), d9 (50 μg)Anti-CTLA-4 monotherapy = ineffective
Anti-CD40 monotherapy = ineffective
Ad-li-GP vaccine = slight survival enhancement
Anti-CTLA-4 + anti-CD40 + ad-li-GP vaccine = 30–40% long-term survival
LungM109/BALB/c (67)UC10-4F10-11; d4, d8, d12(400 μg each) Ixa: d3, d7, d11Anti-CTLA-4 monotherapy = ineffective
Ixabepilone = 50% of mice tumor-free following tumor cell implantation; 20% of mice tumor-tree following tumor rechallenge
Anti-CTLA-4 + ixabepilone = 80% of mice tumor-free following tumor cell implantation; 75% of mice tumor-free following tumor rechallenge
Paclitaxel = 20% of mice tumor-free following tumor cell implantation
Anti-CTLA-4 + paclitaxel = 20% of mice tumor-free following tumor cell implantation tumor cell implantation
PlasmacytomaMOPC-315/BALB/c ANnCrlBr (85)UC10-4F10-11; 20 mm tumors tx daily for 10 days (100 μg each)Anti-CTLA-4 monotherapy = ineffective
Melphalan = 7/39 mice survived
Anti-CTLA-4 + melphalan = 27/37 mice survived