(533h) Normalizing the Tumor Microenvironment for Immunotherapy with Dexamethasone and Tranilast

Cancer cells promote the development of abnormal blood and lymphatic vessels through altered signaling and generation of mechanical stress. These processes create a hostile tumor microenvironment featuring hypoxia, acidity, and elevated interstitial fluid pressure. These abnormalities fuel disease progression, immunosuppression, and treatment resistance¹. Judicious use of antiangiogenesis agents that block altered vascular signaling can transiently ‘normalize’ tumor vessels². In parallel, because desmoplasia collapses vessels, normalizing the extracellular matrix to decompress vessels also can improve their function³. These two strategies may be combined to enhance chemo-, radio-, and immune-therapies⁴.

Here, I will describe our progress in repurposing commonly used drugs to normalize the tumor microenvironment to increase efficacy of immunotherapy⁵. In one approach, we repurposed the anti-hypertensive drug losartan to normalize the extracellular matrix, alleviate hypoxia, and potentiate chemotherapy⁶. Losartan is efficacious in pancreatic cancer patients receiving chemo-radiation⁷and is being tested with immunotherapy (NCT03563248). Because anti-hypertensives might not be safe in hypotensive patients, we reformulated this class of anti-hypertensive drug in a nanocarrier to reduce its intended effect⁸.

In a second approach, we repurposed two drugs already administered to most cancer patients – glucocorticoid steroids and anti-histamines. Using dexamethasone as a model glucocorticoid steroid, we found that a certain dose and schedule can normalize vessels and the extracellular matrix thereby alleviating hypoxia and increasing nanocarrier delivery and efficacy⁹. In parallel, we found that a certain anti-histamine (i.e. tranilast) normalizes the extracellular matrix towards decompressing vessels and increasing nanocarrier and immune checkpoint inhibitor efficacy¹⁰. Outstanding questions regarding combining glucocorticoid steroids with immune checkpoint inhibitors and overcoming resistance in breast cancer lung metastasis will be addressed.

Repurposing drugs to normalize the tumor microenvironment has the potential to rapidly and inexpensively expand the fraction of cancer patients that can benefit from immunotherapy.

References:

1. Martin, J. D.; Fukumura, D.; Duda, D. G.; Boucher, Y.; Jain, R. K., Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity. Cold Spring Harbor Perspectives in Medicine 2016,6, a027094.
2. Chauhan, V. P.; Stylianopoulos, T.; Martin, J. D.; Popovic, Z.; Chen, O.; Kamoun, W. S.; Bawendi, M. G.; Fukumura, D.; Jain, R. K., Normalization of Tumour Blood Vessels Improves the Delivery of Nanomedicines in a Size-Dependent Manner. Nat Nanotechnol 2012,7, 383-388.
3. Stylianopoulos, T.; Martin, J. D.; Chauhan, V. P.; Jain, S. R.; Diop-Frimpong, B.; Bardeesy, N.; Smith, B. L.; Ferrone, C. R.; Hornicek, F. J.; Boucher, Y.; Munn, L. L.; Jain, R. K., Causes, Consequences, and Remedies for Growth-Induced Solid Stress in Murine and Human Tumors. Proc. Natl. Acad. Sci. U. S. A. 2012,109, 15101-15108.
4. Martin, J. D.; Seano, G.; Jain, R. K., Normalizing Function of Tumor Vessels: Progress, Opportunities and Challenges. Annual review of physiology 2019,81, 505-534.
5. Martin, J. D.; Cabral, H.; Stylianopoulos, T.; Jain, R. K., Improving Cancer Immunotherapy Using Nanomedicine: Progress, Opportunities and Challenges. Nat. Rev. Clin. Oncol. 2020,17, 251-266.
6. Chauhan, V. P.; Martin, J. D.; Liu, H.; Lacorre, D. A.; Jain, S. R.; Kozin, S. V.; Stylianopoulos, T.; Mousa, A. S.; Han, X.; Adstamongkonkul, P.; Popovic, Z.; Huang, P.; Bawendi, M. G.; Boucher, Y.; Jain, R. K., Angiotensin Inhibition Enhances Drug Delivery and Potentiates Chemotherapy by Decompressing Tumour Blood Vessels. Nat Commun 2013,4, 2516.
7. Murphy, J. E.; Wo, J. Y.-L.; Ryan, D. P.; Clark, J. W.; Jiang, W.; Yeap, B. Y.; Drapek, L. C.; Ly, L.; Baglini, C. V.; Blaszkowsky, L.; Ferrone, C.; Parikh, A. R.; Weekes, C.; Nipp, R. D.; Kwak, E. L.; Allen, J. N.; Corcoran, R. B.; Ting, D. T.; Faris, J. E.; Zhu, A. X., et al., A Phase Ii Study of Neoadjuvant Folfirinox in Combination with Losartan Followed by Chemoradiotherapy in Locally Advanced Pancreatic Cancer: R0 Resection Rate and Clinical Outcomes. JAMA Oncology 2019,5, 1020-1027.
8. Chauhan, V. P.; Chen, I. X.; Tong, R. T.; Ng, M. R.; Martin, J. D.; Naxerova, K.; Wu, M. W.; Huang, P.; Boucher, Y.; Kohane, D. S.; Langer, R.; Jain, R. K., Reprogramming the Microenvironment with Tumor-Selective Angiotensin Blockers Enhances Cancer Immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2019,116, 10674-10680.
9. Martin, J. D.; Panagi, M.; Wang, C.; Khan, T. T.; Martin, M. R.; Voutouri, C.; Toh, K.; Papageorgis, P.; Mpekris, F.; Polydorou, C.; Ishii, G.; Takahashi, S.; Gotohda, N.; Suzuki, T.; Wilhelm, M. E.; Melo, V. A.; Quader, S.; Norimatsu, J.; Lanning, R. M.; Kojima, M., et al., Dexamethasone Increases Cisplatin-Loaded Nanocarrier Delivery and Efficacy in Metastatic Breast Cancer by Normalizing the Tumor Microenvironment. ACS Nano 2019,13, 6396-6408.
10. Panagi, M.; Voutouri, C.; Mpekris, F.; Papageorgis, P.; Martin, M. R.; Martin, J. D.; Polydorou, C.; Louca, M.; Kataoka, K.; Cabral, H.; Stylianopoulos, T., Tgf-Î’ Inhibition Combined with Cytotoxic Nanomedicine Normalizes Triple Negative Breast Cancer Microenvironment Towards Anti-Tumor Immunity. Theranostics 2020,in press.