CA-170, a first in class oral small molecule dual inhibitor of immune checkpoints PD-L1 and VISTA, demonstrates tumor growth inhibition in pre-clinical models and promotes T cell activation in Phase 1 study

Powderly, John D.; Patel, Manish R.; Lee, J.J.; Brody, Joshua; Meric‐Bernstam, Funda; Hamilton, Erika; Aix, Santiago Ponce; García-Corbacho, Javier; Bang, Y-J.; Ahn, M-J.; Rha, Sun Young; Kim, K-P.; Martin, M.; Wang, H.; Lazorchak, Adam S.; Wyant, Timothy; Ma, Anna; Agarwal, Shefali; Tuck, David; Daud, Adil

doi:10.1093/annonc/mdx376.007

Cited by 46 publications

(31 citation statements)

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“…found that VISTA was detected in all 82 of their endometrial cancer specimens and in 91.3% of their ovarian cancer specimens; they also found that VISTA in tumour cells suppressed T cell proliferation and cytokine production in vitro and decreased tumour‐infiltrating CD8 + T cell counts in vivo . CA‐170, an oral inhibitor of PD‐L1 and VISTA, inhibited tumour growth in preclinical models and also promoted T cell activation in a Phase I study . These data suggest that blocking VISTA may be a promising immunotherapeutic strategy for cancer treatment, including GTN.…”

Section: Discussionmentioning

confidence: 89%

PD‐L1, B7‐H3 and VISTA are highly expressed in gestational trophoblastic neoplasia

et al. 2019

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Aims: The B7 family check-point molecules are potential therapeutic targets in cancer immunotherapy. However, their expression status in human gestational trophoblastic neoplasia (GTN) remains unknown. We investigated the expression profiles of the B7 family check-point proteins PD-L1, PD-L2, B7-H3, B7-H4, VISTA and B7-H6 in GTN and their clinical significance. Methods and results: We identified 112 patients with GTN, including 68 with choriocarcinoma, 33 with placental-site trophoblastic tumour (PSTT) and 11 with epithelioid trophoblastic tumour (ETT). Immunohistochemical staining was performed on whole-tissue GTN sections using anti-B7 family antibodies. VISTA expression was immunohistochemically analysed using microarrays of normal human tissues and of 20 common cancers. PD-L1 and B7-H3 were highly expressed in all GTN tumours, while PD-L2 was expressed in 87.5% of the samples. B7-H4 and B7-H6 were negative in 100% and 98.2% of the samples, respectively. PD-L1, B7-H3 and VISTA levels were significantly higher in choriocarcinomas and PSTTs than in ETTs. There was no association between B7 family check-point expression in tumour cells and disease stage, prognostic score or patient outcomes (complete remission versus death). VISTA protein was widely overexpressed in 98.2% of all the GTN, but its expression varied in other cancer types and was negative in normal adult and fetal tissues except placental trophoblasts and splenic lymphocytes. Conclusions: The GTN trophoblast cells show high expression of PD-L1, B7-H3 and VISTA in a manner that is independent of clinical outcomes. These proteins may be potential immunotherapeutic targets when treating GTN. Thymus (0/3) Colon (0/3) Sternum (0/2) Myocardium (0/5) Spleen (0/5) Lung (0/5) Aorta (0/3) Diaphragm (0/3) Skin (0/5) Kidney (0/4) Ovary (0/1) Hippocampus (0/4) Adrenal (0/5) Bladder (0/3) Stomach (0/5) Small intestine (0/4) Oesophagus (0/2) Testis (0/2) Pancreas (0/5) Liver (0/5) Brain (0/5) Adult organs (number positive/total cores) Oesophagus (0/8) Tongue (0/3) Thyroid (0/14) Small intestine (0/11) Spleen (2/2) Brain (0/6) Bladder (0/4) Skeletal muscle (0/7) Prostate (0/3) Skin (0/3) Colon (0/11) Myocardium (0/3) Lung (0/16) Trachea (0/3) Pancreas (0/8) Seminal vesicle (0/1) Appendix (0/5) Rectum (0/8) Breast (0/5) Uterine cervix (0/10) Testis (0/7) Aorta (0/3) Liver (0/8) Placenta (28/28) Larynx (0/3) Penis (0/5) Uterus (0/4) Stomach (0/14) Kidney (0/5) Cancer samples (number positive/total cores) Brain (0/6) Larynx (1/3) Stomach (0/6) Ureter (1/5) Rectum (0/5) Breast (0/5) Penis (3/5) Thyroid (1/10) Uterus (0/8) Ovary (2/6) Kidney (0/10) Pancreas (0/5) Prostate (0/6) Colon (0/5) Lung (0/7) Oesophagus (0/4) Liver (0/6) Testis (0/3) Bladder (0/6) Uterine cervix (2/8)

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Section: Discussionmentioning

confidence: 89%

PD‐L1, B7‐H3 and VISTA are highly expressed in gestational trophoblastic neoplasia

et al. 2019

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“…In preclinical ex vivo data, CA‐170 demonstrated dose‐dependent enhancement in the proliferation of PD‐L1, PD‐L2, and VISTA‐inhibited T lymphocytes (half‐maximal effective concentration [EC 50 ] = 17, 13, and 37 nM, respectively) and in INF‐γ production . Several subsequent in vivo studies have shown that CA‐170 can activate both peripheral and intratumoral T lymphocytes at doses of 10 and 100 mg/kg . CA‐170 administered orally on a once‐daily schedule could significantly reduce the number of B16/F10 melanoma lung metastases and the growth rate of implanted mouse MC38 colon carcinoma tumors .…”

Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…In 2016, this drug candidate became the first small molecule to be progressed into phase 1 clinical trials for the treatment of advanced solid tumors and lymphoma . Emerging clinical data from a small number of patients show early signs of antitumor activity, including tumor shrinkages and prolonged stable disease, with an acceptable safety profile and approximately dose proportional PK profile . The most promising feature of CA‐170 is that it exhibits sustained immune pharmacodynamics (PD) in vitro and in vivo, suggesting that drug efficacy may extend beyond drug clearance …”

Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

155

121

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Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

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“…Initial results are promising without any dose-limiting toxicities and showing peripheral T-cell expansion. 165 …”

Section: Reversing Inhibitory Signalsmentioning

confidence: 99%

New strategies in immunotherapy for lung cancer: beyond PD-1/PD-L1

Villanueva

Bazhenova

2018

Ther Adv Respir Dis

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Immunotherapy has significantly altered the treatment landscape for many cancers, including non-small cell lung cancer (NSCLC). Currently approved immuno-oncology agents for lung cancer are aimed at the reversal of immune checkpoints, programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1). Although responses to checkpoint inhibitors are encouraging, and in some cases durable, these successes are not universal among all treated patients. In order to optimize our treatment approach utilizing immunotherapy, we must better understand the interaction between cancer and the immune system and evasion mechanisms. In this review, we will provide an overview of the immune system and cancer, and review novel therapies that promote tumor antigen release for immune system detection, activate the effector T-cell response, and reverse inhibitory antitumor signals.

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CA-170, a first in class oral small molecule dual inhibitor of immune checkpoints PD-L1 and VISTA, demonstrates tumor growth inhibition in pre-clinical models and promotes T cell activation in Phase 1 study

Cited by 46 publications

References 0 publications

PD‐L1, B7‐H3 and VISTA are highly expressed in gestational trophoblastic neoplasia

PD‐L1, B7‐H3 and VISTA are highly expressed in gestational trophoblastic neoplasia

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

New strategies in immunotherapy for lung cancer: beyond PD-1/PD-L1

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