A Phase 1, Open-Label, Dose-Escalation Study of L-DOS47 in Combination With Pemetrexed Plus Carboplatin in Patients With Stage IV Recurrent or Metastatic Nonsquamous NSCLC

Piha‐Paul, Sarina A.; Simon, George R.; Belani, Chandra P.; Chao, Heman; Gaspar, Kim; Lee, Brenda; Dowlati, Afshin

doi:10.1016/j.jtocrr.2022.100408

Cited by 5 publications

(6 citation statements)

References 19 publications

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“…Conversely, L-DOS47 has been proven safe and well tolerated in phase I/IIa clinical trials in heavily pretreated NSCLC patients, both as a monotherapy and in combination with pemetrexed and carboplatin [20,48]. Encouraging progression-free survival and clinical benefit were observed, particularly in patients who were also receiving pemetrexed/carboplatin (41.7% in objective response rate and 75% in clinical benefit).…”

Section: Discussionmentioning

confidence: 99%

“…Its mechanism of action involves selective binding to CEACAM6 on the tumor cell surface, thereby localizing urease, which converts endogenous urea into NH 3 and CO 2 with a net production of bicarbonate and hydroxyl ions and causes alkalinization of the extracellular tumor microenvironment (TME). In phase I clinical trials, L-DOS47 was well tolerated in patients with non-small-cell lung cancer (NSCLC) and yielded encouraging results when combined with pemetrexed plus carboplatin, with 75% of patients showing clinical benefits (stable disease, complete response, or partial response) [20]. Since L-DOS47 is suitable for cancers that express high levels of its target antigen CEACAM6, pancreatic and gastrointestinal cancers are other potential applications in addition to lung cancer [21,22].…”

Section: Introductionmentioning

confidence: 99%

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L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy

Jardim-Perassi,

Irrera,

Oluwatola

et al. 2024

Biomedicines

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Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer–magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy

Jardim-Perassi,

Irrera,

Oluwatola

et al. 2024

Biomedicines

View full text Add to dashboard Cite

show abstract

“…Conversely, L-DOS47 has been proven safe and well tolerated in Phase I/IIa clinical trials in heavily pretreated NSCLC patients both as a monotherapy and in combination with pemetrexed and carboplatin [22,43]. Encouraging progression-free survival and clinical benefit were observed, particularly in patients also receiving pemetrexed/carboplatin (41.7% objective response rate and 75% clinical benefit).…”

Section: Discussionmentioning

confidence: 99%

“…Its mechanism of action involves selective binding to CEACAM6 on the tumor cell surface, localizing the urease, which converts endogenous urea into NH3 and CO2 with the net production of bicarbonate and hydroxyl ions and causes alkalinization of the extracellular tumor microenvironment (TME). In Phase I clinical trials, L-DOS47 was well tolerated in patients with non-small-cell lung cancer (NSCLC) and yielded encouraging results when combined with pemetrexed plus carboplatin, with 75% of patients showing clinical benefit (stable disease, complete or partial response) [22]. Since L-DOS47 is suitable for cancers that express high levels of its target antigen CEACAM6, pancreatic and gastrointestinal cancers are potential other applications in addition to lung cancer [23,24].…”

Section: Introductionmentioning

confidence: 99%

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor

Jardim-Perassi,

Irrera,

Abrahams

et al. 2023

Preprint

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Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

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“…Interfering with net acid extrusion from solid tumors is a promising treatment approach [ 22 ] but lack of specific pharmacological compounds has restricted preclinical development. Previous experimental interventions—in addition to genetic interference with acid-base targets in rodents—include ingestion of weak base (e.g., HCO 3 – or TRIS) [ 23 , 24 ] or combined intravital enzymatic release of weak acid and base [ 25 ] to increase buffering power at the tumor site and attenuate microenvironment acidity. However, oral dosing with NaHCO 3 carry substantial, mainly gastrointestinal, adverse effects that reduce patient compliance and have resulted in clinical trial discontinuation [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Antibodies toward Na+,HCO3–-cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer

Axelsen,

Olesen,

Khan

et al. 2024

Br J Cancer

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Background Na+,HCO3–-cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. Methods We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3–-cotransport with human breast cancer metastasis. Results We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3–-cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3–-cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. Conclusions Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth.

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A Phase 1, Open-Label, Dose-Escalation Study of L-DOS47 in Combination With Pemetrexed Plus Carboplatin in Patients With Stage IV Recurrent or Metastatic Nonsquamous NSCLC

Cited by 5 publications

References 19 publications

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor

Antibodies toward Na+,HCO3–-cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer

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