Agents targeting costimulatory receptors | |||||
Costimulatory receptor | Receptor class | Agent, mechanism of action | Pharmaceutical | Trial | Outcomes |
CD28 | Ig | TGN1412 CD28 “superagonist” | TeGenero | Phase I NHS (2006) | Cytokine storm in initial six patients |
TAB08, theralizumab (rebranded TGN1412) | TheraMAB | Phase I, advanced tumors, NCT03006029 | NA | ||
REGN5678 PSMA x CD28 | Regeneron | Phase I/II, mCRPC, plus cemiplimab, NCT03972657 | Dose-dependent reduction in PSA with moderate antitumor activity in higher-dose cohorts | ||
FPT155 CD80 Fc fusion protein, blocks CTLA-4 from competing for endogenous CD80 | Five Prime, Amgen | Phase I, advanced tumors,±pembrolizumab, NCT04074759 | NA | ||
ALPN-202, davoceticept, CD80 vIgD-Fc fusion protein & dual PD-1/CTLA-4 inhibitor | Alpine | Phase I (NEON-1), advanced tumors NCT04186637 | 2/48 PR, 23/48 SD | ||
Phase I (NEON-2), plus pembrolizumab, NCT04920383 | Terminated (two grade 5 AEs) | ||||
4-1BB (CD137) | TNF | BMS-663513, urelumab, agonist mAb | BMS | Phase I, advanced tumors (NCT00309023), and melanoma (NCT00612664) | Enrollment paused at higher doses due to severe hepatotoxicity; lower doses tolerable but efficacy similar to anti-PD1 |
Phase I, advanced CRC or H&N, plus cetuximab, NCT02110082 | Only biomarker analysis reported | ||||
Phase I/II (INTRUST), advanced tumors, intratumoral urelumab, plus nivolumab, NCT03792724 | NA | ||||
Phase I, PDAC, neoadjuvant/adjuvant GVAX, nivolumab, urelumab, NCT02451982 | Non-significant improvement in DFS with urelumab addition | ||||
PF-05082566, utomilumab, agonist mAb | Pfizer | Phase I, advanced tumors, NCT01307267 | 2/55 CR/PR | ||
Phase I, advanced CRC, plus irinotecan, cetuximab, NCT03290937 | NA | ||||
Phase I, advanced tumors, plus anti-CCR4, NCT02444793 | Terminated | ||||
Phase I, ovarian cancer, plus TIL therapy+aldesleukin, NCT03318900 | NA | ||||
Phase II, HPV+HNSCC, plus ISA101b vaccine, NCT03258008 | NA | ||||
GEN1046 4-1BB x PD-L1 | Genmab, BioNTech | Phase I, advanced tumors, NCT03917381 | 40/61 PR or SD | ||
Phase II, advanced NSCLC,±pembrolizumab, NCT05117242 | NA | ||||
NM21-1480 4-1BB x PD-L1 x HSA | Numab | Phase I/II, advanced tumors, NCT04442126 | NA | ||
DSP107 4-1BB x SIRPα | KAHR | Phase I, advanced tumors,±atezolizumab, NCT04440735 | 11/22 SD in dose-escalation phase | ||
OX40 | TNF | MEDI0562 agonist mAb | MedImmune, AstraZeneca | Phase I, advanced tumors, NCT02318394 | 2/55 PR, 24/55 SD |
Phase I, advanced tumors, plus durvalumab or tremelimumab, NCT02705482 | Minimal single-agent or combination benefit | ||||
Phase I, neoadjuvant HNSCC or melanoma, NCT03336606 | NA | ||||
BMS-986178 agonist mAb | BMS | Phase I/II, advanced tumors,±nivolumab and/or ipilimumab, NCT02737475 | No objective response in monotherapy; up to 13% response in combination cohorts | ||
Phase I, advanced tumors, plus TLR9-agonist, NCT03831295 | NA | ||||
BGB-A445 agonist mAb | BeiGene | Phase I/II, advanced tumors,±tislelizumab, NCT04215978 | NA | ||
MOXR0916 agonist mAb | Genentech | Phase I, advanced tumors, NCT02219724 | 2/173 PR, 57/173 SD | ||
Phase I, advanced tumors, plus atezolizumab, NCT02410512 | 11/70 SD | ||||
PF-04518600, ivuxolimab, agonist mAb | Pfizer | Phase I/II, advanced tumors, avelumab±ivuxolimab +/- utomilumab±radiation NCT03217747 | NA | ||
Phase I, advanced tumors±utomilumab, NCT02315066 | 14/57 SD | ||||
ICOS | Ig | JTX-2011, vopratelimab, agonist mAb | Jounce | Phase I/II, advanced tumors.±nivolumab, pembrolizumab, or ipilimumab, ICONIC, NCT02904226 | Preliminary antitumor activity with nivolumab |
Phase II (EMERGE), NSCLC or urothelial cancer, plus ipilimumab, NCT03989362 | Minimal benefit | ||||
Phase II, TISvopra+NSCLC, anti-PD1±JTX-2011, SELECT, NCT04549025 | Minimal benefit versus anti-PD1 alone | ||||
GSK3359609, feladilimab, agonist mAb | GSK | Phase II (INDUCE-3), PD-L1 positive HNSCC, plus pembrolizumab, NCT04128696 | Terminated | ||
Phase II/III (INDUCE-4), recurrent/metastatic HNSCC, GSK3359609 versus placebo plus pembrolizumab & chemo, NCT04428333 | Terminated | ||||
Phase I/II, advanced tumors, plus trememlimumab, NCT03693612 | NA | ||||
GITR | TNF | INCAGN-1876 agonist mAb | Incyte, Agenus | Phase I/II, advanced tumors, NCT02697591 | NA |
Phase I/II, advanced tumors,±nivolumab/ipilimumab, NCT03126110 | NA | ||||
Phase II, HNSCC, plus retifanlimab (PD1), NCT05359692 | NA | ||||
Phase II, GBM, plus retifanlimab (PD1), NCT04225039 | NA | ||||
BMS-986156 agonist mAb | BMS | Phase I/II, advanced tumors,±nivolumab, NCT02598960 | Preliminary antitumor activity in combination cohort | ||
Phase I/II, advanced lung or liver, ipilimumab, nivolumab±radiation, NCT04021043 | NA | ||||
GWN323 agonist mAb | Novartis | Phase I, advanced tumors,±spartalizumab, NCT02740270 | Minimal single-agent benefit; 18/45 with disease control in combination cohort | ||
TRX518 agonist mAb | Leap | Phase I, advanced tumors, NCT01239134 | Minimal single-agent benefit | ||
Phase I, advanced tumors, plus gemcitabine, pembrolizumab, or nivolumab NCT02628574 | Minimal monotherapy or combination benefit | ||||
CD27 | TNF | CDX-1127, varlilumab, agonist mAb | Celldex | Phase I, advanced tumors, NCT01460134 (CDX) | 1/31 PR; 8/31 SD in advanced solid tumors |
Phase I/II, advanced tumors, plus nivolumab, NCT02335918 | Response similar to nivolumab monotherapy | ||||
Phase I, advanced tumors, plus atezolizumab, NCT02543645 | Terminated | ||||
Phase I/II, stage IIB-IV melanoma, 6MHP vaccination±CDX-1127, NCT03617328 | NA | ||||
MK-5890 agonist mAb | Merck | Phase I, advanced tumors,±pembrolizumab, NCT03396445 | 4/14 CR/PR in combination cohort | ||
Phase II, advanced NSCLC, KEYMAKER-U01C substudy, NCT04165096 | NA | ||||
CD40 | TNF | RO7009789, selicrelumab, agonist mAb | Hoffmann-La Roche | Phase I, advanced tumors, plus atezolizumab, NCT02304393 | No improvement compared with anti-PD1 monotherapy |
Phase I, advanced tumors, plus anti-CSF1R, NCT02760797 | No objective clinical benefit | ||||
Phase I, advanced tumors, plus anti-VEGF, NCT02665416 | NA | ||||
CDX-1140 agonist mAb | Celldex | Phase I, advanced tumors,±Flt3 L, pembrolizumab, or chemotherapy, NCT03329950 | NA | ||
Phase I, IB-IV melanoma (including uveal), plus neoantigen vaccines and TLR-agonist NCT04364230 | NA | ||||
Phase I, TNBC, plus Flt3L, chemo, NCT05029999 | NA | ||||
Phase I, advanced NSCLC, plus Flt3L, radiation, NCT04491084 | NA | ||||
Phase I, advanced epithelial cancers, TSA-reactive TCR-engineered T cells, pembrolizumab, NCT04520711 | NA | ||||
APX005M, sotigalimab, agonist mAb | Apexigen | Phase I/I, advanced NSCLC or melanoma, plus nivolumab, NCT03123783 | 6/33 PR, 3/33 SD | ||
Phase I, untreated PDAC, plus chemo±nivolumab, NCT02482168 | 14/30 PR, 8/30 SD | ||||
Phase II, untreated PDAC, plus chemo±nivolumab, NCT03214250 | 1-year OS 57.3% (APX005M+chemo+nivolumab), p=0.007, n=34 | ||||
Phase II, resectable neoadjuvant esophageal adenocarcinoma, plus chemo, radiation, NCT03165994 | NA | ||||
Phase I, advanced melanoma or RCC, plus nivolumab/ipilimumab, NCT04495257 | NA | ||||
ChiLob7/4 agonist mAb | University of Southampton, UK | Phase I, advanced tumors, NCT01561911 | SD in 15/29 treatments | ||
SEA-CD40 agonist mAb | Seagen | Phase I, advanced tumors,±pembrolizumab, or±pembrolizumab and chemo, NCT02376699 | NA |
AE, adverse event; CR, complete response; DFS, disease-free survival; mAb, monoclonal antibody; OS, overall survival; PR, partial response; SD, stable disease; TNF, tumor necrosis factor; TSA, tumor-specific antigen.