Abstract SY33-01: Improving immunotherapy of cancer by normalizing tumor vessels
Authors: Jain Rakesh K. 
Published: August 2019

Abstract
Advances in immunotherapy have revolutionized treatment of multiple solid tumors - aptly recognized by the 2018 Nobel Prize for Medicine to Drs. James Allison and Tasuko Honjo. Their respective discoveries of CTLA4 and PD1 - two immune checkpoint molecules that serve as “brakes” on the immune cells - have led to the approval of multiple immune-checkpoint blockers (ICB) for multiple cancer types. ICBs disable the brakes and unleash the patient’s immune response against their cancer (e.g., melanoma, lung cancer, bladder cancer, head-and-neck cancer). Another immunotherapy that has revolutionized the treatment of a number of “liquid” cancers - and has the potential to do so for solid tumors - involves re-engineering and expanding the immune cells of the patient outside the body (ex vivo) so that they can recognize antigen molecules displayed on the surface of cancer cells and kill these cancer cells once injected back in the patient’s blood stream. However, these breakthrough treatments are efficacious only in a fraction of cancer patients and can cause serious adverse effects. Emerging data show that blood vessels that nourish the tumor are a critical determinant of whether the treatment will elicit immune response or not. Blood vessels not only govern the delivery of endogenous and exogenous immune cells to tumors, but also their function after these immune cells extravasate from blood vessels and enter the tumor microenvironment (TME). Our overarching hypothesis is that improving the function of the tumor vasculature can improve therapeutic outcome and reduce toxicity associated with various immunotherapeutic approaches. Using intravital microscopy and animal models of primary and metastatic tumors, our laboratory has shown that tumor blood vessels are structurally and functionally abnormal. Abnormal vessels create a hostile metabolic and physical tumor microenvironment, characterized by hypoxia, low pH and high interstitial fluid pressure. These abnormalities can impair delivery of antibodies and immune cells in tumors, compromise their efficacy after they accrue in tumors, and, independent of these, fuel tumor progression and metastasis and induce immunosuppression [1, 2]. To overcome these challenges, we have also identified the molecular and physical mechanisms that cause vascular abnormalities [1, 2, 3]. Based on this knowledge, we have developed two broad strategies to improve the function of tumor vessels - (a) normalizing vessels with judicious use of antiangiogenic agents and decompressing vessels using widely prescribed angiotensin-system inhibitors or drugs approved for other indications (e.g., plerixafor) [1, 2, 3]. We and others have tested these strategies in a number of pre-clinical studies in the past decade and demonstrated that normalizing the function of tumor vessels can convert the immunosuppressive TME into an immunostimulatory melieu and improve the delivery and efficacy of vaccines, antibodies and ICBs [4-12]. Moreover, emerging data from randomized phase III trials supports this concept [13]. A recent study also demonstrated that ICBs may also normalize blood vessels in certain tumor models [14]. If ICB-mediated vessel normalization is induced across a range of tumour types, this mechanism may further enhance the benefit of vascular normalization using antiangiogenic and/or decompressing agents for various immunotherapies and reduce their adverse effects [10,15].
REFERENCES:
1. RK Jain. Normalizing Tumor Vasculature with Anti-Angiogenic Therapy: A New Paradigm for Combination Therapy. Nature Medicine,7: 987-989 (2001).
2. RK Jain. Normalization of the tumor vasculature: An emerging concept in anti-angiogenic therapy of cancer. Science307: 58-62 (2005).
3. RK Jain. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell26: 605-622 (2014).
4. Y Huang et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunetherapy. PNAS, 109:17561-6 (2012).
5. TE Peterson TE et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. PNAS 113:4470-5 (2016).
6. J Kloepper J et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. PNAS 113:4476-81 (2016).
7. VP Chauhan et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Nature Communications 4: 2516 (2013).
8. H Liu et al. Use of Angiotensin System Inhibitors is Associated with Immune Activation and Longer Survival in Non-Metastatic Pancreatic Ductal Adenocarcinoma. Clinical Cancer Research.23(19):5959-5969 (2017).
9. M Pinter and RK Jain. Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy. Science Translational Medicine9: eaan5616 (2017).
10. D Fukumura, J Kloepper, Z Amoozgar, DG Duda and RK Jain. Enhancing Cancer Immunotherapy Using Antiangiogenics: Opportunities and Challenges. Nature Reviews Clinical Oncology15(5):325-340 (2018).
11. IX Chen et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. PNAS(2019).
12. VP Chauhan et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. PNAS(2019)
13. MA Socinski MA et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301 (2018).
14. L Tianet al.Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature544, 250-254, doi:10.1038/nature21724 (2017).
15. M De Palma and RK Jain. CD4 T cell activation and vascular normalization: Two sides of the same coin? Immunity46: 773-5 (2017).
Citation Format: Rakesh K. Jain. Improving immunotherapy of cancer by normalizing tumor vessels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY33-01.