436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRI
OBJECTIVES/GOALS: Acidity and the lactate-to-pyruvate ratio correlate with immunotherapy resistance. AcidoCEST MRI and hyperpolarized magnetic resonance spectroscopy (HP-MRS) measure extracellular pH and lactate-to-pyruvate ratio. We will establish a baseline for these biomarkers then observe change...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Cambridge University Press
2024-04-01
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| Series: | Journal of Clinical and Translational Science |
| Online Access: | https://www.cambridge.org/core/product/identifier/S2059866124003765/type/journal_article |
| _version_ | 1797226878815174656 |
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| author | Grace Abigail Murley Shivanand Pudakalakatti William Padron Muxin Wang Ryan Armijo Jorge Delacerda Abishai Dominic Renee Chin William Schuler Kunal Rai Marty Pagel Pratip Bhattacharya |
| author_facet | Grace Abigail Murley Shivanand Pudakalakatti William Padron Muxin Wang Ryan Armijo Jorge Delacerda Abishai Dominic Renee Chin William Schuler Kunal Rai Marty Pagel Pratip Bhattacharya |
| author_sort | Grace Abigail Murley |
| collection | DOAJ |
| description | OBJECTIVES/GOALS: Acidity and the lactate-to-pyruvate ratio correlate with immunotherapy resistance. AcidoCEST MRI and hyperpolarized magnetic resonance spectroscopy (HP-MRS) measure extracellular pH and lactate-to-pyruvate ratio. We will establish a baseline for these biomarkers then observe changes after combination esomeprazole and immunotherapy. METHODS/STUDY POPULATION: We used multiple melanoma models created via serial in vivo passage under immunotherapeutic pressure (FVAX, CTLA-4, PD-1, PD-L1). We used four of these corresponding to 25%, 50%, 75% and 100% resistance (TMT, F2, F3, and F4, respectively). HP-MRS was performed two weeks post implantation in male BL6 mice with AcidoCEST MRI 2-3 days later. Tumors were implanted in additional mice and grown for 1 week. We used esomeprazole as a possible immunotherapy sensitizer. Esomeprazole (or PBS) alone and in combination with immune checkpoint blockade (ICB; αCTLA-4, αPD-1) was then conducted every 3 days for 3 doses. ICB was administered 3h after esomeprazole. AcidoCEST MRI was performed the day after the final dose of combination therapy and 3h after esomeprazole (or PBS) alone. HP-MRS was performed 2-3 days after acidoCEST MRI. RESULTS/ANTICIPATED RESULTS: There was a statistical increase in the lactate-to-pyruvate ratio of the F4 group compared with TMT, F2, and F3 groups (p < 0.05). The TMT, F2, and F3 groups did not differ significantly. The extracellular pH (pHe) of the TMT group was statistically lower than the F2 and F4 groups (p < 0.05). The pHe did not differ significantly between the TMT and F3 groups nor the F2, F3, and F4 groups. The lactate-to-pyruvate ratio and pHe after combination treatment with esomeprazole and ICB did not differ compared to PBS+ICB control. Treatment with esomeprazole alone generated higher lactate-to-pyruvate ratio compared with PBS alone. Tumor volume curves and survival curves of mice bearing F4 tumors treated with esomeprazole combination with ICB showed no difference compared with PBS+ICB, PBS alone, and esomeprazole alone. DISCUSSION/SIGNIFICANCE: We differentiated between the 100% and 25% resistant models with both pHe and lactate-to-pyruvate ratio, although the pHe was counterintuitive. Esomeprazole was ineffective, but other potential sensitizers exist. A non-invasive clinical imaging tool and sensitizer would permit more personalized treatment plans so treatment is more effective. |
| first_indexed | 2024-04-24T14:31:55Z |
| format | Article |
| id | doaj.art-3f11af4ec4b64a67b87e245bed7e36f8 |
| institution | Directory Open Access Journal |
| issn | 2059-8661 |
| language | English |
| last_indexed | 2024-04-24T14:31:55Z |
| publishDate | 2024-04-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | Journal of Clinical and Translational Science |
| spelling | doaj.art-3f11af4ec4b64a67b87e245bed7e36f82024-04-03T02:00:15ZengCambridge University PressJournal of Clinical and Translational Science2059-86612024-04-01813013010.1017/cts.2024.376436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRIGrace Abigail Murley0Shivanand Pudakalakatti1William Padron2Muxin Wang3Ryan Armijo4Jorge Delacerda5Abishai Dominic6Renee Chin7William Schuler8Kunal Rai9Marty Pagel10Pratip Bhattacharya11UTHealth GSBS/MD Anderson Cancer CenterMD Anderson Cancer CenterMD Anderson Cancer CenterMD Anderson Cancer CenterMD Anderson Cancer CenterMD Anderson Cancer CenterMD Anderson Cancer Centerthe University of Texas Health Science Center at Houston, MD Anderson Cancer CenterMD Anderson Cancer Centerthe University of Texas Health Science Center at Houston, MD Anderson Cancer Centerthe University of Texas Health Science Center at Houston, MD Anderson Cancer Centerthe University of Texas Health Science Center at Houston, MD Anderson Cancer CenterOBJECTIVES/GOALS: Acidity and the lactate-to-pyruvate ratio correlate with immunotherapy resistance. AcidoCEST MRI and hyperpolarized magnetic resonance spectroscopy (HP-MRS) measure extracellular pH and lactate-to-pyruvate ratio. We will establish a baseline for these biomarkers then observe changes after combination esomeprazole and immunotherapy. METHODS/STUDY POPULATION: We used multiple melanoma models created via serial in vivo passage under immunotherapeutic pressure (FVAX, CTLA-4, PD-1, PD-L1). We used four of these corresponding to 25%, 50%, 75% and 100% resistance (TMT, F2, F3, and F4, respectively). HP-MRS was performed two weeks post implantation in male BL6 mice with AcidoCEST MRI 2-3 days later. Tumors were implanted in additional mice and grown for 1 week. We used esomeprazole as a possible immunotherapy sensitizer. Esomeprazole (or PBS) alone and in combination with immune checkpoint blockade (ICB; αCTLA-4, αPD-1) was then conducted every 3 days for 3 doses. ICB was administered 3h after esomeprazole. AcidoCEST MRI was performed the day after the final dose of combination therapy and 3h after esomeprazole (or PBS) alone. HP-MRS was performed 2-3 days after acidoCEST MRI. RESULTS/ANTICIPATED RESULTS: There was a statistical increase in the lactate-to-pyruvate ratio of the F4 group compared with TMT, F2, and F3 groups (p < 0.05). The TMT, F2, and F3 groups did not differ significantly. The extracellular pH (pHe) of the TMT group was statistically lower than the F2 and F4 groups (p < 0.05). The pHe did not differ significantly between the TMT and F3 groups nor the F2, F3, and F4 groups. The lactate-to-pyruvate ratio and pHe after combination treatment with esomeprazole and ICB did not differ compared to PBS+ICB control. Treatment with esomeprazole alone generated higher lactate-to-pyruvate ratio compared with PBS alone. Tumor volume curves and survival curves of mice bearing F4 tumors treated with esomeprazole combination with ICB showed no difference compared with PBS+ICB, PBS alone, and esomeprazole alone. DISCUSSION/SIGNIFICANCE: We differentiated between the 100% and 25% resistant models with both pHe and lactate-to-pyruvate ratio, although the pHe was counterintuitive. Esomeprazole was ineffective, but other potential sensitizers exist. A non-invasive clinical imaging tool and sensitizer would permit more personalized treatment plans so treatment is more effective.https://www.cambridge.org/core/product/identifier/S2059866124003765/type/journal_article |
| spellingShingle | Grace Abigail Murley Shivanand Pudakalakatti William Padron Muxin Wang Ryan Armijo Jorge Delacerda Abishai Dominic Renee Chin William Schuler Kunal Rai Marty Pagel Pratip Bhattacharya 436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRI Journal of Clinical and Translational Science |
| title | 436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRI |
| title_full | 436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRI |
| title_fullStr | 436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRI |
| title_full_unstemmed | 436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRI |
| title_short | 436 Immunotherapy Sensitization via Tumor Acidosis Mitigation by Esomeprazole Monitored with MRI |
| title_sort | 436 immunotherapy sensitization via tumor acidosis mitigation by esomeprazole monitored with mri |
| url | https://www.cambridge.org/core/product/identifier/S2059866124003765/type/journal_article |
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