ATo date, certain problems have been identiified in cancer immunotherapy based onusing the inhibition of immune checkpoints (ICs) is an actively developing field of study, and it has been widely used. Antibodies blocking immune checkpoints are used as therapeutics. The targeted checkpoints are mainly . Despite the excellent effect of cancer therapy in some cases when blocking the PD-L1 (programmed death-ligand 1), expressed by the tumor, and the ligand and the immune cell receptors PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) immune cell receptors. To increase the effectiveness of therapy by blocking ICs,with antibodies, the proportion of patients responding to such therapy is still far from desirable. This situation has stimulated the exploration of additional receptors and ligands are being investigated as s targets offor immunotherapy.
Receptor | Results of Preclinical Stydies | Ligands | Clinical Significance/ Results of Preclinical Stydies |
---|---|---|---|
Target | Drug | Number of Current Trials/ Phase |
Type of Tumor | Some Published Results of Clinical Trials | ||||
---|---|---|---|---|---|---|---|---|
Trial | Clinical Safety and Efficacy | |||||||
TIM-3 | The use of mAbs against TIM-3 stimulates the production of IFNγ. The antitumor efficacy of anti-TIM-3 is associated with the ratio of CD8+:CD4+ T-cells in the TILs pool. The combined use of mAbs targeting TIM-3, PD-1 (programmed cell death protein 1), and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) has has been shown to be more effective and well tolerated [42][47]. In models of lung adenocarcinoma, it was found that the use of mAbs targeting PD-1 can increase the expression of TIM-3. The effectiveness of the use of TIM-3 in overcoming resistance to therapy with mAbs targeting PD-1 has been shown [43][48]. The expression of LAG-3 and CTLA-4 was increased on CD8+ T-lymphocytes bound by the used mAbs targeting TIM-3 and PD-1. The combined use of mAbs targeting TIM-3 and CTLA-4 shows a synergistic effect in models [44][49]. |
Phosphotidylserine | - | |||||
Galectin-9 | ||||||||
TIM-3 | Sabatolimab (MBG453) |
16 I, II, III |
Advanced or metastatic solid tumors Bone marrow diseases Glioblastoma Hematologic malignancies |
NCT02608268 Phase I-Ib/II |
Patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. No responses were seen with sabatolimab. Five patients receiving combination treatment had PR (6%; lasting 12–27 months) [51] |
Resistance to anti-PD-1 therapy has been observed in the presence of TIM-3+ lymphocytes and galectin-9-expressing myeloid-derived suppressor cells (MDSC) [45][17]. The co-expression of galectin-9 and TIM-3 has been detected in various types of cancer [46][47][14,19]. The correlation of galectin-9 expression with better overall survival (OS) (in hepatocellular carcinoma (HCC) and colorectal cancer (CRC)) or progression-free survival (PFS) (in gastric cancer (GC) (in HCC and CRC) or PFS (in GC and NSCLC) has been shown [48][20]. The opposite data are available [49][16]. |
||
TSR-022Alarmin-1 (HMGB1) |
HMGB1 is associated with progression and metastasis in NSCLC and CRC [50][51][25,26]. | |||||||
4 I, II |
CEACAM1 | A synergistic antitumor effect has been shown with the simultaneous blockade of TIM-3 and CEACAM1, as well as CEACAM1 and PD-L1 (programmed death-ligand 1), on CRC models [52][36]. In the early stages of CRC, CEACAM1 inhibits tumor cell proliferation [53][34]. However, CEACAM1 is a diagnostic and prognostic marker in melanoma, and CEACAM1 is found in tumor samples and sera from patients with pancreatic cancer (PC) and is overexpressed in advanced stages of CRC, NSCLC, and other cancers [54][39]. | ||||||
Advanced or metastatic solid tumors | Melanoma | NCT02817633 Phase I |
In the group of 20 patients who received the TSR-022+TSR-042 combination, the ORR was 15% (3/20), and disease stabilization reached 40% (8/20) [52]. |
|||||
LY3321367 | 1 I |
Solid tumors | NCT03099109 Phase I |
No DLTs were observed in the monotherapy (n = 30) or combination (n = 28) therapy. LY3321367 TRAEs occurred in ≥2 patients. In the NSCLC monotherapy expansion cohort, outcomes varied: anti-PD-1/L1 refractory patients [N = 23, ORR 0%, DCR 35%, PFS 1.9 months] versus anti-PD-1/L1 responders (n = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (n = 91), ORR and DCR were 4% and 42% [53] |
||||
LY3415244, BsAb for PD-L1/TIM-3 |
1 I |
Advanced solid tumors | NCT03752177 Phase Ia/Ib |
Two patients (16.7%) developed clinically significant anaphylactic infusion-related reactions. One patient with PD-1 refractory NSCLC had a near partial response (−29.6%) [54] |
LAG-3 | It has been shown that the therapeutic use of PD-1 leads to an increase in the expression level of LAG-3 [55][80]. In NSCLC, the co-expression of LAG-3 and PD-1 on TILs and PD-L1 on tumor cells is shown [56][81]. A synergistic effect was observed from the combined use of mAbs binds LAG-3 and PD-1 in various tumor models [57][82]. | MHC class II | MHC class |
INCAGN02390 | II | molecule (MHCII) | 5 | is associated with survival, increased numbers of CD4+ and CD8+ T -cells in the TILs, and a good response to anti-PD-1 and PD-L1 immunotherapy in some cancers [58][65]. | ||||
I | Solid tumors Melanoma |
- | - | Fibrinogen-like protein (FGL-1) | The FGL-1/LAG-3 interaction blockade stimulates tumor immunity [59][67]. The reduced expression of FGL-1 increases the efficiency of CD8+ T-cell activation during LAG-3 blockade [ | |||
BGB-A425 | 60][69]. | |||||||
1 I |
Advanced or metastatic solid tumors | - | - | Galectin-3 | The restoration of cytolytic functions of CD8+ T- cells in response to the inhibition of galectin-3 was shown, which indicates the role of galectin-3 in the suppression of antitumor immunity. The direct involvement of galectin-3 in the processes of metastasis was revealed [61][62][63][72,73,74], as well as the association of galectin-3 expression with poor clinical prognosis [64][75 | |||
BMS-986258 | ]. However, in melanoma and glioblastoma, the presence of galectin-3 is beneficial for patients [65][76]. | |||||||
1 I |
Advanced cancer | - | - | LSECtin | A high level of soluble LSECtin in the blood serum of patients with CRC is associated with the presence of liver metastases [66][78]. The expression of LSECtin and its interaction with LAG-3 molecules are shown on B16 melanoma cells. It is accompanied by the suppression of the T-cell antitumor response, and the blockade of LSECtin/LAG-3 interaction restores the secretion of IFNγ [67][79]. | |||
SHR-1702 | 2 I |
Hematologic malignancies Advanced solid tumors | - | - | TIGIT | The blockade of TIGIT has been shown to prevent the depletion of NK cells and stimulate NK-mediated tumor immunity, activate antitumor T-cell immunity, and promote the formation of immune memory [68][69][122,129]. The co-inhibition of TIGIT and PD-1 or PD-L1 with mAbs exhibited a significant therapeutic effect, up to the complete elimination of tumors [68][70][71][72][122,124,125,126]. Using mAb against TIGIT showed: restoration of the functions of effector T-cells; the induction of cellular cytotoxicity against regulatory T-cells; a direct cytotoxic effect on TIGIT+ tumor cells [ | ||
RO7121661, BsAb for PD-1/TIM-3 | 73][74][127,130]. The high efficiency of the combined inhibition of PD-1 and CD96 or TIGIT and CD96 has been shown [75][128]. | Nectin-2 (CD112) |
2 I, II | Interaction with TIGIT leads to the corresponding transmission of inhibitory signals to immune cells. Nectin-2 is expressed in breast and ovarian tumors [76][111]. | ||||
Advanced or metastatic solid tumors | Melanoma |
- | - | Nectin-4 (PVRL4) |
Nectin-4 blocking Abs stimulates an NK-mediated antitumor response [77][113]. The participation of nectin-4 in the processes of proliferation, invasion, and metastasis through the activation of Pi3k/Akt and WNT/β-catenin signaling pathways has been shown [78][114]. The revealed hyperexpression of nectin-4 by tumor tissues is associated with tumor aggressiveness and poor clinical prognosis [79][80][115,116]. | |||
LAG-3 | Eftilagimod alpha (IMP321) | 14 I, II |
Advanced or metastatic solid tumors Melanoma |
NCT00732082 Phase I |
None of the 6 patients received 0.5 mg IMP321 experienced TRAEs. Of the 5 patients who received IMP321 at the 2 mg dose level, 1 experienced rash, 1 reported hot flashes, and 2 had mild pain at the injection sites [85] |
PVR (CD155) |
||
NCT00349934 Phase I | Overexpression and the presence of a soluble form of CD155 in the blood serum of patients are associated with a poor clinical prognosis [81][82][83][102,106,107]. The association of the co-expression of TIGIT and CD155 with an unfavorable disease course in lung adenocarcinoma and primary SCC of the esophagus has been shown [82][84][106,108]. | |||||||
Thirty patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Additionally, t he ORR of 50% compared favorably to the 25% rate reported in the historical control group [86]. |
VISTA | In response to blocking VISTA with the use of mAbs, an increase in the number of TILs and the restoration of the functions of CD8+ T-cells were observed [32][147]. An increase in the expression of chemokines (CXCL9/10, CCL4/5) as well as cytokines (IFNβ, IL6, IL12, IL23, IL27, TNFα) was observed in tumor tissues [31][146]. However, the effective suppression of tumor growth was observed only when anti-VISTA mAbs was used in combination with anti-PD-1 mAbs [85][86][171,173] or CTLA-4 [87][170]. The blockade of VISTA caused an increase in tumor infiltration by immune cells and a decrease in the number of myeloid suppressor cells (MSCs). The therapeutic effect of anti-VISTA antibodies has been demonstrated in ovarian cancer (OC) models highly expressing VISTA [28][143]. |
VSIG-3 (IGSF11) |
|||||
Favezelimab (MK-4280) |
10 I, II, III | The expression of VSIG-3 by tumor tissues was found in CRC, HCC, and in intestinal-type GC [88][151]. The overexpression of VSIG-3 is associated with the expression of VISTA, as well as with PD-L1 and PD-1, with a high degree of tumor malignancy, and a poor clinical prognosis in glioblastoma has been revealed [89][152]. Experimental models show the antitumor efficacy of the SG7 Ab, which inhibits VISTA binding to VSIG-3 and PSGL-1 [90][174]. |
||||||
Advanced or metastatic solid tumors | Hematologic malignancies Melanoma |
NCT03598608 Phase I/II |
Fifteen patients received MK-4280 with pembrolizumab, four of whom achieved a partial response [87] |
PSGL-1 | The ability of PSGL-1 to bind to VISTA was shown at acidic values of the medium (pH 6.0). At lower pH values, an enhanced inhibitory effect of VISTA was shown, and the use of Abs capable of blocking the VISTA/PSGL-1 interaction restored the proliferative and secretory functions of T-cells [91] | |||
Relatlimab (BMS-986016) | [153]. Experimental models show the antitumor efficacy of the SG7 Ab, which inhibits VISTA binding to VSIG-3 and PSGL-1 [90][174]. |
|||||||
31 I, II |
Advanced or metastatic solid tumors Hematologic malignancies Melanoma |
NCT01968109 Phase I/IIa |
Patients received relatlimab + nivolumab. In 61 efficacy-evaluable patients, ORR was 11.5% (1 complete, 6 partial (1 unconfirmed) responses); DCR was 49%. Median DOR was not reached (min [0.1þ], max [39.3þ]). ORR was 3.5-fold higher in patients with LAG-3 expression, 1% vs. <1%, regardless of PD-L1 expression. TRAEs occurred in 41% |
Galectin-9 | The study of samples from patients with peritoneal carcinomatosis showed a high level of expression of galectin-9, VISTA and TIM-3 depleted TILs [92][156]. | |||
(gr 3/4, 4.4%; DC, 1.5%) [ | 89 | BTLA | The antitumor efficacy of anti-BTLA mAbs has been shown [93][94][212,213]. In the blockade of BTLA, an increase in the proliferation and expansion of NY-ESO-1-specific CD8+ T-cells was observed, and an increased efficiency of the use of mAbs targeting BTLA in combination with anti-PD-1 and anti-Tim-3 in melanoma was shown [95][214]. An increase in median OS [96][215], as well as the enhancing T-cell proliferation and cytokine production, was observed with the combination of anti-BTLA and anti-PD-1 therapies [97][216]. | HVEM (TNFRSF14) |
T-cell activation is observed as a result of HVEM suppression in OC cells and in the ESCC cell line [98][99][195,196]. HVEM expression is associated with a decrease in the number of TILs and with a poor prognosis in ESCC and CRC, including in patients with CRC metastases to the liver and other oncological diseases [99]196[100][,198101][,199102][103][,200,201]. The high expression of HVEM is associated with an increased risk of transformation, while transformed FL is characterized by a low level of BTLA expression and a high level of HVEM [104][202]. In GC, an overexpression of BTLA and HVEM is associated with a poor clinical prognosis [105][203]. |
] | |||||
NCT03470922 | |||||
Phase II | |||||
The median PFS was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab–nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; | |||||
p | |||||
= 0.006 by the log-rank test). PFS at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab–nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Grade 3 or 4 TRAEs occurred in 18.9% of patients in the relatlimab–nivolumab group and in 9.7% of patients in the nivolumab group [ | |||||
90 | |||||
]. | |||||
TSR-033 | 2 I |
Advanced solid tumors | - | - | |
REGN3767 | 5 I, II, III |
Advanced solid tumors | - | - | |
Ieramilimab (LAG525) | 5 I, II |
Advanced solid tumors Hematologic malignancies Melanoma |
NCT02460224 Phase I/II |
Patients received fermilab (n = 134) or fermilab + spartalizumab (n = 121). Four patients experienced DLT in each treatment arm. No MTD was reached. TRAEs occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Seven patients experienced SAEs in the single-agent (5%) and combination groups (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) CR and 10 (8%) PR. In the combination arm, 8 patients (6.6%) experienced SD for 6 months or longer versus 6 patients (4.5%) in the single-agent arm [93] |
|
FS118, BsAb for LAG-3/PD-L1 |
1 I, II |
Advanced solid tumors Hematologic malignancies Melanoma |
- | - | |
RO7247669, BsAb for LAG-3/PD-1 |
5 I, II |
Advanced or metastatic solid tumors Melanoma |
- | - | |
TIGIT | Vibostolimab (MK-7684) |
15 I, II, III |
Advanced or metastatic solid tumors Melanoma Hematologic malignancies |
NCT02964013 Phase I |
Part A: 56% of patients receiving monotherapy and 62% receiving a combination of vibostolimab with pembrolizumab had TRAEs. Grade 3–4 TRAEs occurred in 9% and 17% of patients, respectively. No DLT was reported. The confirmed ORR was 0% for monotherapy and 7% for combination therapy. Part B: 39 patients had anti-PD-1/PD-L1-naive NSCLC, and all received combination therapy. TRAEs occurred in 85% of patients. The confirmed ORR was 26%, with responses observed in both PD-L1-positive and PD-L1-negative tumors. Sixty-seven had anti-PD-1/PD-L1-refractory NSCLC, and 56% receiving monotherapy and 70% receiving combination therapy had TRAEs. The confirmed ORR was 3% for monotherapy and 3% for combination therapy [131] |
BMS-986207 | 4 I, II |
Advanced solid tumors Multiple myeloma |
- | - | |
Etigilimab (OMP-313M32) |
2 I, II |
Advanced or metastatic solid tumors | NCT03119428 Phase Ia/Ib |
Thirty-three patients were enrolled (Phase Ia, n = 23; Phase Ib, n = 10). There was no DLT. MTD was not determined. Six patients experienced grade ≥ 3 TRAEs. In Phase Ia, 7 patients (30.0%) had stable disease. In Phase Ib, 1 patient had a PR; 1 patient had prolonged SD of nearly 8 months. Median PFS was 56.0 days (Phase Ia) and 57.5 days (Phase Ib) [133] |
|
Tiragolumab | 38 I, II, III |
Advanced or metastatic solid tumors Melanoma Hematologic malignancies |
NCT02864992 Phase II |
The RR by independent review was 46% (95% CI, 36 to 57), with a median DoR of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The RR was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed RR was 56% (95% CI, 45 to 66). TRAEs of grade ≥ 3 were reported in 28% [134] |
|
NCT03563716 Phase II |
Patients were randomly assigned to receive tiragolumab + atezolizumab (67 (50%)) or placebo + atezolizumab (68 (50%)). After a median follow-up of 5.9 months (4.6–7.6, in the intention-to-treat population, 21 patients (31.3% [95% CI 19.5–43.2]) in the tiragolumab + atezolizumab group versus 11 patients (16.2% [6.7–25.7]) in the placebo + atezolizumab group had an objective response (p = 0.031). Median PFS was 5.4 months (95% CI 4.2-not estimable) in the tiragolumab + atezolizumab group versus 3·6 months (2.7–4.4) in the placebo + atezolizumab group (stratified hazard ratio 0.57 [95% CI 0.37–0.90], p = 0.015). Fourteen (21%) patients receiving tiragolumab + atezolizumab and 12 (18%) patients receiving placebo + atezolizumab had SAEs [135] |
||||
Domvanalimab (AB154) |
9 I, II, III |
Advanced or metastatic solid tumors Melanoma Glioblastoma |
- | - | |
ASP8374 | 3 I |
Advanced solid tumors Glioblastoma |
- | - | |
VISTA | CI-8993 | 1 I |
Solid tumors | - | - |
CA-170, VISTA/PD-L1/2 antagonist | 2 I, II |
Advanced or metastatic solid tumors lymphomas |
NCT02812875 Phase I |
According to the RECIST, 33 out of 50 patients who received CA-170 showed SD. PR or CR was not achieved. Severe (grade 3 and 4) TRAEs were observed in 5 patients. No DLTs were observed [171]. | |
JNJ-61610588 | 1 I |
Advanced or metastatic solid tumors | - | - | |
BTLA | TAB004/JS004 | 7 I, II |
Recurrent/ refractory malignant lymphoma Advanced or metastatic solid tumors |
- | |
Target | Drug | Number of Current Trials/ Phase |
Type of Tumor | Some Published Results of Clinical Trials | |
---|---|---|---|---|---|
Trial | Clinical Safety and Efficacy | ||||
TIM-3 | Sabatolimab (MBG453) |
16 I, II, III |
Advanced or metastatic solid tumors Bone marrow diseases Glioblastoma Hematologic malignancies |
NCT02608268 Phase I-Ib/II |
Patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. No responses were seen with sabatolimab. Five patients receiving combination treatment had PR (6%; lasting 12–27 months) [106] |
TSR-022 | 4 I, II |
Advanced or metastatic solid tumors Melanoma |
NCT02817633 Phase I |
In the group of 20 patients who received the TSR-022+TSR-042 combination, the ORR was 15% (3/20), and disease stabilization reached 40% (8/20) [107]. |
|
LY3321367 | 1 I |
Solid tumors | NCT03099109 Phase I |
No DLTs were observed in the monotherapy (n = 30) or combination (n = 28) therapy. LY3321367 treatment-related adverse events (TRAEs) occurred in ≥2 patients. In the NSCLC monotherapy expansion cohort, outcomes varied: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, DCR 35%, PFS 1.9 months] versus anti-PD-1/L1 responders (n = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (n = 91), ORR and DCR were 4% and 42% [108] |
|
LY3415244, BsAb for PD-L1/TIM-3 |
1 I |
Advanced solid tumors | NCT03752177 Phase Ia/Ib |
Two patients (16.7%) developed clinically significant anaphylactic infusion-related reactions. One patient with PD-1 refractory NSCLC had a near partial response (−29.6%) [109] |
|
INCAGN02390 | 5 I |
Solid tumors Melanoma |
- | - | |
BGB-A425 | 1 I |
Advanced or metastatic solid tumors | - | - | |
BMS-986258 | 1 I |
Advanced cancer | - | - | |
SHR-1702 | 2 I |
Hematologic malignancies Advanced solid tumors | - | - | |
RO7121661, BsAb for PD-1/TIM-3 |
2 I, II |
Advanced or metastatic solid tumors Melanoma |
- | - | |
LAG-3 | Eftilagimod alpha (IMP321) | 14 I, II |
Advanced or metastatic solid tumors Melanoma |
NCT00732082 Phase I |
None of the 6 patients received 0.5 mg IMP321 experienced TRAEs. Of the 5 patients who received IMP321 at the 2 mg dose level, 1 experienced rash, 1 reported hot flashes, and 2 had mild pain at the injection sites [110] |
NCT00349934 Phase I |
Thirty patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Additionally, t he ORR of 50% compared favorably to the 25% rate reported in the historical control group [111]. |
||||
Favezelimab (MK-4280) |
10 I, II, III |
Advanced or metastatic solid tumors Hematologic malignancies Melanoma |
NCT03598608 Phase I/II |
Fifteen patients received MK-4280 with pembrolizumab, four of whom achieved a partial response [112] |
|
Relatlimab (BMS-986016) |
31 I, II |
Advanced or metastatic solid tumors Hematologic malignancies Melanoma |
NCT01968109 Phase I/IIa |
Patients received relatlimab + nivolumab. In 61 efficacy-evaluable patients, ORR was 11.5% (1 complete, 6 partial (1 unconfirmed) responses); DCR was 49%. Median DOR was not reached (min [0.1þ], max [39.3þ]). ORR was 3.5-fold higher in patients with LAG-3 expression, 1% vs. <1%, regardless of PD-L1 expression. TRAEs occurred in 41% (gr 3/4, 4.4%; DC, 1.5%) [113] |
|
NCT03470922 Phase II |
The median PFS was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab–nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; p = 0.006 by the log-rank test). PFS at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab–nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Grade 3 or 4 TRAEs occurred in 18.9% of patients in the relatlimab–nivolumab group and in 9.7% of patients in the nivolumab group [114]. | ||||
TSR-033 | 2 I |
Advanced solid tumors | - | - | |
REGN3767 | 5 I, II, III |
Advanced solid tumors | - | - | |
Ieramilimab (LAG525) | 5 I, II |
Advanced solid tumors Hematologic malignancies Melanoma |
NCT02460224 Phase I/II |
Patients received fermilab (n = 134) or fermilab + spartalizumab (n = 121). Four patients experienced DLT in each treatment arm. No MTD was reached. TRAEs occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Seven patients experienced SAEs in the single-agent (5%) and combination groups (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) CR and 10 (8%) PR. In the combination arm, 8 patients (6.6%) experienced SD for 6 months or longer versus 6 patients (4.5%) in the single-agent arm [115] |
|
FS118, BsAb for LAG-3/PD-L1 |
1 I, II |
Advanced solid tumors Hematologic malignancies Melanoma |
- | - | |
RO7247669, BsAb for LAG-3/PD-1 |
5 I, II |
Advanced or metastatic solid tumors Melanoma |
- | - | |
TIGIT | Vibostolimab (MK-7684) |
15 I, II, III |
Advanced or metastatic solid tumors Melanoma Hematologic malignancies |
NCT02964013 Phase I |
Part A: 56% of patients receiving monotherapy and 62% receiving a combination of vibostolimab with pembrolizumab had TRAEs. Grade 3–4 TRAEs occurred in 9% and 17% of patients, respectively. No DLT was reported. The confirmed ORR was 0% for monotherapy and 7% for combination therapy. Part B: 39 patients had anti-PD-1/PD-L1-naive NSCLC, and all received combination therapy. TRAEs occurred in 85% of patients. The confirmed ORR was 26%, with responses observed in both PD-L1-positive and PD-L1-negative tumors. Sixty-seven had anti-PD-1/PD-L1-refractory NSCLC, and 56% receiving monotherapy and 70% receiving combination therapy had TRAEs. The confirmed ORR was 3% for monotherapy and 3% for combination therapy [116] |
BMS-986207 | 4 I, II |
Advanced solid tumors Multiple myeloma |
- | - | |
Etigilimab (OMP-313M32) |
2 I, II |
Advanced or metastatic solid tumors | NCT03119428 Phase Ia/Ib |
Thirty-three patients were enrolled (Phase Ia, n = 23; Phase Ib, n = 10). There was no DLT. MTD was not determined. Six patients experienced grade ≥ 3 TRAEs. In Phase Ia, 7 patients (30.0%) had stable disease. In Phase Ib, 1 patient had a PR; 1 patient had prolonged SD of nearly 8 months. Median PFS was 56.0 days (Phase Ia) and 57.5 days (Phase Ib) [117] |
|
Tiragolumab | 38 I, II, III |
Advanced or metastatic solid tumors Melanoma Hematologic malignancies |
NCT02864992 Phase II |
The RR by independent review was 46% (95% CI, 36 to 57), with a median DoR of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The RR was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed RR was 56% (95% CI, 45 to 66). TRAEs of grade ≥ 3 were reported in 28% [118] |
|
NCT03563716 Phase II |
Patients were randomly assigned to receive tiragolumab + atezolizumab (67 (50%)) or placebo + atezolizumab (68 (50%)). After a median follow-up of 5.9 months (4.6–7.6, in the intention-to-treat population, 21 patients (31.3% [95% CI 19.5–43.2]) in the tiragolumab + atezolizumab group versus 11 patients (16.2% [6.7–25.7]) in the placebo + atezolizumab group had an objective response (p = 0.031). Median PFS was 5.4 months (95% CI 4.2-not estimable) in the tiragolumab + atezolizumab group versus 3·6 months (2.7–4.4) in the placebo + atezolizumab group (stratified hazard ratio 0.57 [95% CI 0.37–0.90], p = 0.015). Fourteen (21%) patients receiving tiragolumab + atezolizumab and 12 (18%) patients receiving placebo + atezolizumab had SAEs [119] |
||||
Domvanalimab (AB154) |
9 I, II, III |
Advanced or metastatic solid tumors Melanoma Glioblastoma |
- | - | |
ASP8374 | 3 I |
Advanced solid tumors Glioblastoma |
- | - | |
VISTA | CI-8993 | 1 I |
Solid tumors | - | - |
CA-170, VISTA/PD-L1/2 antagonist | 2 I, II |
Advanced or metastatic solid tumors lymphomas |
NCT02812875 Phase I |
According to the RECIST, 33 out of 50 patients who received CA-170 showed SD. PR or CR was not achieved. Severe (grade 3 and 4) TRAEs were observed in 5 patients. No DLTs were observed [85]. | |
JNJ-61610588 | 1 I |
Advanced or metastatic solid tumors | - | - | |
BTLA | TAB004/JS004 | 7 I, II |
Recurrent/ refractory malignant lymphoma Advanced or metastatic solid tumors |
- |