Light-enhanced VEGF/rGel Induce Immunogenic Cell Death and Increase the Antitumor Activity of αCTLA4 Treatment

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Jan 4

PMID 38173721

Authors

Ane Sager Longva

Kristian Berg

Anette Weyergang

Affiliations

Soon will be listed here.

Abstract

Background: Immune-checkpoint inhibitors (ICIs) represent a revolution in cancer therapy and are currently implemented as standard therapy within several cancer indications. Nevertheless, the treatment is only effective in a subset of patients, and immune-related adverse effects complicate the improved survival. Adjuvant treatments that can improve the efficacy of ICIs are highly warranted, not only to increase the response rate, but also to reduce the therapeutic ICI dosage. Several treatment modalities have been suggested as ICI adjuvants including vascular targeted treatments and photodynamic therapy (PDT). Photochemical internalization (PCI) is a drug delivery system, based on PDT. PCI is long known to generate an immune response in murine models and was recently shown to enhance the cellular immune response of a vaccine in a clinical study. In the present work we evaluated PCI in combination with the vascular targeting toxin VEGF/rGel with respect to induction of immune-mediated cell death as well as ICI enhancement.

Methods: DAMP signaling post VEGF/rGel-PCI was assessed in CT26 and MC38 murine colon cancer cell lines. Hypericin-PDT, previously indicated as an highly efficient DAMP inducer (but difficult to utilize clinically), was used as a control. ATP release was detected by a bioluminescent kit while HMGB1 and HSP90 relocalization and secretion was detected by fluorescence microscopy and western blotting. VEGF/rGel-PCI was further investigated as an αCTLA enhancer in CT26 and MC38 tumors by measurement of tumor growth delay. CD8+ Dependent efficacy was evaluated using a CD8+ antibody.

Results: VEGF/rGel-PCI was shown to induce increased DAMP signaling as compared to PDT and VEGF/rGel alone and the magnitude was found similar to that induced by Hypericin-PDT. Furthermore, a significant CD8+ dependent enhanced αCTLA-4 treatment effect was observed when VEGF/rGel-PCI was used as an adjuvant in both tumor models.

Conclusions: VEGF/rGel-PCI describes a novel concept for ICI enhancement which induces a rapid CD8+ dependent tumor eradication in both CT26 and MC38 tumors. The concept is based on the combination of intracellular ROS generation and vascular targeting using a plant derived toxin and will be developed towards clinical utilization.

Citing Articles

Enhancing antitumour immunity with photodynamic therapy.

Selbo P, Korbelik M Photochem Photobiol Sci. 2025; 24(2):227-234.

PMID: 39971873 DOI: 10.1007/s43630-025-00690-2.

Photosensitive Hybrid γδ-T Exosomes for Targeted Cancer Photoimmunotherapy.

Gao Y, Liu J, Wu M, Zhang Y, Wang M, Lyu Q ACS Nano. 2025; 19(4):4251-4268.

PMID: 39862206 PMC: 11803918. DOI: 10.1021/acsnano.4c11024.

Cellular Imaging and Time-Domain FLIM Studies of Meso-Tetraphenylporphine Disulfonate as a Photosensitising Agent in 2D and 3D Models.

Balukova A, Bokea K, Barber P, Ameer-Beg S, MacRobert A, Yaghini E Int J Mol Sci. 2024; 25(8).

PMID: 38673807 PMC: 11050357. DOI: 10.3390/ijms25084222.

References

Weyergang A, Fremstedal A, Skarpen E, Peng Q, Mohamedali K, Eng M . Light-enhanced VEGF/rGel: A tumor targeted modality with vascular and immune-mediated efficacy. J Control Release. 2018; 288:161-172. DOI: 10.1016/j.jconrel.2018.09.005. View

Kleinovink J, Fransen M, Lowik C, Ossendorp F . Photodynamic-Immune Checkpoint Therapy Eradicates Local and Distant Tumors by CD8 T Cells. Cancer Immunol Res. 2017; 5(10):832-838. DOI: 10.1158/2326-6066.CIR-17-0055. View

Garg A, Krysko D, Vandenabeele P, Agostinis P . Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol Immunother. 2011; 61(2):215-221. PMC: 11029694. DOI: 10.1007/s00262-011-1184-2. View

Shams M, Owczarczak B, Manderscheid-Kern P, Bellnier D, Gollnick S . Development of photodynamic therapy regimens that control primary tumor growth and inhibit secondary disease. Cancer Immunol Immunother. 2014; 64(3):287-97. PMC: 4341021. DOI: 10.1007/s00262-014-1633-9. View

Weyergang A, Cheung L, Rosenblum M, Mohamedali K, Peng Q, Waltenberger J . Photochemical internalization augments tumor vascular cytotoxicity and specificity of VEGF(121)/rGel fusion toxin. J Control Release. 2014; 180:1-9. DOI: 10.1016/j.jconrel.2014.02.003. View

Grigalavicius M, Mastrangelopoulou M, Arous D, Juzeniene A, Menard M, Skarpen E . Photodynamic Efficacy of Cercosporin in 3D Tumor Cell Cultures. Photochem Photobiol. 2020; 96(3):699-707. DOI: 10.1111/php.13257. View

Garg A, Krysko D, Verfaillie T, Kaczmarek A, Ferreira G, Marysael T . A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 2012; 31(5):1062-79. PMC: 3298003. DOI: 10.1038/emboj.2011.497. View

ODonnell J, Teng M, Smyth M . Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol. 2018; 16(3):151-167. DOI: 10.1038/s41571-018-0142-8. View

Wong J, Berstad M, Fremstedal A, Berg K, Patzke S, Sorensen V . Photochemically-Induced Release of Lysosomal Sequestered Sunitinib: Obstacles for Therapeutic Efficacy. Cancers (Basel). 2020; 12(2). PMC: 7072415. DOI: 10.3390/cancers12020417. View

10.

Robert C, Thomas L, Bondarenko I, ODay S, Weber J, Garbe C . Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364(26):2517-26. DOI: 10.1056/NEJMoa1104621. View

11.

Mohamedali K, Ran S, Gomez-Manzano C, Ramdas L, Xu J, Kim S . Cytotoxicity of VEGF(121)/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2. BMC Cancer. 2011; 11:358. PMC: 3176242. DOI: 10.1186/1471-2407-11-358. View

12.

Duan X, Chan C, Guo N, Han W, Weichselbaum R, Lin W . Photodynamic Therapy Mediated by Nontoxic Core-Shell Nanoparticles Synergizes with Immune Checkpoint Blockade To Elicit Antitumor Immunity and Antimetastatic Effect on Breast Cancer. J Am Chem Soc. 2016; 138(51):16686-16695. PMC: 5667903. DOI: 10.1021/jacs.6b09538. View

13.

Gollnick S, Brackett C . Enhancement of anti-tumor immunity by photodynamic therapy. Immunol Res. 2009; 46(1-3):216-26. PMC: 2831137. DOI: 10.1007/s12026-009-8119-4. View

14.

Johnson D, Nebhan C, Moslehi J, Balko J . Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022; 19(4):254-267. PMC: 8790946. DOI: 10.1038/s41571-022-00600-w. View

15.

He C, Duan X, Guo N, Chan C, Poon C, Weichselbaum R . Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat Commun. 2016; 7:12499. PMC: 4992065. DOI: 10.1038/ncomms12499. View

16.

Thorgersen E, Asvall J, Froysnes I, Schjalm C, Larsen S, Dueland S . Increased Local Inflammatory Response to MOC31PE Immunotoxin After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. Ann Surg Oncol. 2021; 28(9):5252-5262. PMC: 8349350. DOI: 10.1245/s10434-021-10022-0. View

17.

Leshem Y, King E, Mazor R, Reiter Y, Pastan I . SS1P Immunotoxin Induces Markers of Immunogenic Cell Death and Enhances the Effect of the CTLA-4 Blockade in AE17M Mouse Mesothelioma Tumors. Toxins (Basel). 2018; 10(11). PMC: 6265743. DOI: 10.3390/toxins10110470. View

18.

Georganaki M, van Hooren L, Dimberg A . Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer. Front Immunol. 2019; 9:3081. PMC: 6309238. DOI: 10.3389/fimmu.2018.03081. View

19.

Cramer G, Moon E, Cengel K, Busch T . Photodynamic Therapy and Immune Checkpoint Blockade. Photochem Photobiol. 2020; 96(5):954-961. DOI: 10.1111/php.13300. View

20.

Trojan J, Hoffmeister A, Neu B, Kasper S, Dechene A, Jurgensen C . Photochemical Internalization of Gemcitabine Is Safe and Effective in Locally Advanced Inoperable Cholangiocarcinoma. Oncologist. 2022; 27(6):430-e433. PMC: 9177099. DOI: 10.1093/oncolo/oyab074. View