The Tumor Environment in Peritoneal Carcinomatosis and Malignant Pleural Effusions: Implications for Therapy
Abstract
Simple Summary
Abstract
1. Introduction
1.1. Peritoneal Carcinomatosis
1.2. Malignant Pleural Effusions
2. Role of Immune Infiltrating Cells in Cavitary Malignancies
2.1. Immune Cell Infiltration
2.2. T-Cell Exhaustion Versus Quiescence
2.3. Evidence That Cavitary Infiltrating T Cells in Malignancy Are Quiescent Rather than Exhausted
2.4. Mechanisms of Cavitary Immune Suppression
2.5. Summary
3. Key Cytokines of the PC and MPE Tumor Environment
3.1. The IL-6 Axis
3.2. IL-10
3.3. TGFβ
3.4. IL-1RA
3.5. Cellular Mechanisms of Cavitary Immunosuppression
3.6. Summary
4. Tumor–Stromal Interactions
5. Immunotherapy of PC and MPE
5.1. Antibody-Based Immunotherapy of PC and MPE
5.1.1. Anti-PD1
5.1.2. Anti-CTLA-4
5.1.3. Anti-VEGF
5.1.4. Anti-IL6 Receptor
5.2. Bispecific Antibodies
5.3. Oncolytic Viruses
5.4. Summary
6. Cellular Therapeutic Strategies for MPE and PC Treatment
6.1. Tumor-Infiltrating Lymphocytes
6.2. CAR-T Cell Therapy
6.3. Intracavitary TIL Cell Therapy
6.4. Fast TIL
6.5. Summary
7. Conclusions and Future Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
ACT | Adoptive cellular therapy |
B-ALL | B-cell acute lymphoblastic leukemia |
Breg | Regulatory B cells |
CAF | Cancer-associated fibroblast |
CAR | chimeric antigen receptors |
CAR-T | Chimeric antigen receptor T cell |
CEA | Carcinoembronic antigen |
CLL | Chronic lymphocytic leukemia |
CRS | Cytokine release syndrome |
ECM | Extracellular matrix |
EGF | Epidermal growth factor |
EMT | Epithelial-to-mesenchymal transition |
FDA | Food and Drug Administration |
FOXP1 | Forkhead box protein 1 |
HER2 | Human epidermal growth factor receptor 2 |
HIPEC | Hyperthermic intraperitoneal chemotherapy |
ICM | Immune checkpoint molecules |
IFN | Interferon |
IL | Interleukin |
IND | Investigational new drug |
IPC | Indwelling pleural catheter |
LDC | Lymphodepleting chemotherapy |
MA | Malignant ascites |
mAb | Monoclonal antibody |
MDSC | Myeloid-derived suppressor cells |
MHC | Major histocompatibility complex |
MMT | Mesothelial-to-mesenchymal transition |
MPE | Malignant pleural effusion |
MPM | Malignant pleural mesothelioma |
NK | Natural killer |
NSCLC | Non-small cell lung cancer |
PAMP | Pathogen-associated molecular patterns |
PC | Peritoneal carcinomatosis |
TCR | T cell receptor |
TGF | Transforming growth factor |
TIL | Tumor-infiltrating lymphocytes |
TNF | Tumor necrosis factor |
Treg | Regulatory T cells |
VEGF | Vascular endothelial growth factor |
References
- Guan, X. Cancer metastases: Challenges and opportunities. Acta Pharm. Sin. B 2015, 5, 402–418. [Google Scholar] [CrossRef]
- Chu, D.Z.; Lang, N.P.; Thompson, C.; Osteen, P.K.; Westbrook, K.C. Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer 1989, 63, 364–367. [Google Scholar] [CrossRef]
- Kerscher, A.G.; Chua, T.C.; Gasser, M.; Maeder, U.; Kunzmann, V.; Isbert, C.; Germer, C.T.; Pelz, J.O.W. Impact of peritoneal carcinomatosis in the disease history of colorectal cancer management: A longitudinal experience of 2406 patients over two decades. Br. J. Cancer 2013, 108, 1432–1439. [Google Scholar] [CrossRef] [PubMed]
- Bashour, S.I.; Mankidy, B.J.; Lazarus, D.R. Update on the diagnosis and management of malignant pleural effusions. Respir. Med. 2022, 196, 106802. [Google Scholar] [CrossRef]
- Donnenberg, V.S.; Luketich, J.D.; Sultan, I.; Lister, J.; Bartlett, D.L.; Ghosh, S.; Donnenberg, A.D. A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells. Front. Immunol. 2023, 14, 1157697. [Google Scholar] [CrossRef] [PubMed]
- Lewis, C.R.; Dadgar, N.; Yellin, S.A.; Donnenberg, V.S.; Donnenberg, A.D.; Bartlett, D.L.; Allen, C.J.; Wagner, P.L. Regional Immunotherapy for Peritoneal Carcinomatosis in Gastroesophageal Cancer: Emerging Strategies to Re-Condition a Maladaptive Tumor Environment. Cancers 2023, 15, 5107. [Google Scholar] [CrossRef] [PubMed]
- Ornella, M.S.C.; Badrinath, N.; Kim, K.-A.; Kim, J.H.; Cho, E.; Hwang, T.-H.; Kim, J.-J. Immunotherapy for Peritoneal Carcinomatosis: Challenges and Prospective Outcomes. Cancers 2023, 15, 2383. [Google Scholar] [CrossRef]
- Terri, M.; Trionfetti, F.; Montaldo, C.; Cordani, M.; Tripodi, M.; Lopez-Cabrera, M.; Strippoli, R. Mechanisms of Peritoneal Fibrosis: Focus on Immune Cells–Peritoneal Stroma Interactions. Front. Immunol. 2021, 12, 607204. [Google Scholar] [CrossRef]
- Rudralingam, V.; Footitt, C.; Layton, B. Ascites matters. Ultrasound 2017, 25, 69–79. [Google Scholar] [CrossRef]
- Szadkowska, M.A.; Pałucki, J.; Cieszanowski, A. Diagnosis and treatment of peritoneal carcinomatosis—A comprehensive overview. Pol. J. Radiol. 2023, 88, 89–97. [Google Scholar] [CrossRef]
- Dadgar, N.; Sherry, C.; Zimmerman, J.; Park, H.; Lewis, C.; Donnenberg, A.; Zaidi, A.H.; Fan, Y.; Xiao, K.; Bartlett, D.; et al. Targeting interleukin-6 as a treatment approach for peritoneal carcinomatosis. J. Transl. Med. 2024, 22, 402. [Google Scholar] [CrossRef]
- Sangisetty, S.L.; Miner, T.J. Malignant ascites: A review of prognostic factors, pathophysiology and therapeutic measures. World J. Gastrointest. Surg. 2012, 4, 87–95. [Google Scholar] [CrossRef] [PubMed]
- Berger, J.M.; Preusser, M.; Berghoff, A.S.; Bergen, E.S. Malignant ascites: Current therapy options and treatment prospects. Cancer Treat. Rev. 2023, 121, 102646. [Google Scholar] [CrossRef] [PubMed]
- Donnenberg, A.D.; Luketich, J.D.; Donnenberg, V.S. Secretome of pleural effusions associated with non-small cell lung cancer (NSCLC) and malignant mesothelioma: Therapeutic implications. Oncotarget 2019, 10, 6456–6465. [Google Scholar] [CrossRef] [PubMed]
- Gayen, S. Malignant Pleural Effusion: Presentation, Diagnosis, and Management. Am. J. Med. 2022, 135, 1188–1192. [Google Scholar] [CrossRef]
- Porcel, J.M.; Light, R.W. Diagnostic Approach to Pleural Effusion in Adults. Am. Fam. Physician 2006, 73, 1211–1220. [Google Scholar]
- Musso, V.; Diotti, C.; Palleschi, A.; Tosi, D.; Aiolfi, A.; Mendogni, P. Management of Pleural Effusion Secondary to Malignant Mesothelioma. J. Clin. Med. 2021, 10, 4247. [Google Scholar] [CrossRef]
- Gonnelli, F.; Hassan, W.; Bonifazi, M.; Pinelli, V.; Bedawi, E.O.; Porcel, J.M.; Rahman, N.M.; Mei, F. Malignant pleural effusion: Current understanding and therapeutic approach. Respir. Res. 2024, 25, 47. [Google Scholar] [CrossRef]
- Baguneid, A.; Wijayaratne, T.; Aujayeb, A.; Panchal, R. The Evolution of the Indwelling Pleural Catheter. Pulm. Ther. 2025, 11, 519–533. [Google Scholar] [CrossRef]
- Zamboni, M.M.; da Silva, C.T.; Baretta, R.; Cunha, E.T.; Cardoso, G.P. Important prognostic factors for survival in patients with malignant pleural effusion. BMC Pulm. Med. 2015, 15, 29. [Google Scholar] [CrossRef]
- Rathod, S. Chapter Two—T cells in the peritoneum. In International Review of Cell and Molecular Biology; Aranda, F., Berraondo, P., Galluzzi, L., Eds.; Academic Press: Cambridge, MA, USA, 2022; Volume 371, pp. 15–41. [Google Scholar]
- Budna, J.; Kaczmarek, M.; Kolecka-Bednarczyk, A.; Spychalski, Ł.; Zawierucha, P.; Goździk-Spychalska, J.; Nowicki, M.; Batura-Gabryel, H.; Sikora, J. Enhanced Suppressive Activity of Regulatory T Cells in the Microenvironment of Malignant Pleural Effusions. J. Immunol. Res. 2018, 2018, 9876014. [Google Scholar] [CrossRef] [PubMed]
- Kubicka, U.; Olszewski, W.L.; Tarnowski, W.; Bielecki, K.; Ziółkowska, A.; Wierzbicki, Z. Normal human immune peritoneal cells: Subpopulations and functional characteristics. Scand. J. Immunol. 1996, 44, 157–163. [Google Scholar] [CrossRef]
- Noppen, M.; De Waele, M.; Li, R.; Gucht, K.V.; D’Haese, J.; Gerlo, E.; Vincken, W. Volume and cellular content of normal pleural fluid in humans examined by pleural lavage. Am. J. Respir. Crit. Care Med. 2000, 162 Pt 1, 1023–1026. [Google Scholar] [CrossRef]
- Liu, T.; Liu, F.; Peng, L.W.; Chang, L.; Jiang, Y.M. The Peritoneal Macrophages in Inflammatory Diseases and Abdominal Cancers. Oncol. Res. 2018, 26, 817–826. [Google Scholar] [CrossRef]
- Kaczmarek, M.; Sikora, J. Macrophages in malignant pleural effusions—Alternatively activated tumor associated macrophages. Contemp. Oncol. 2012, 16, 279–284. [Google Scholar] [CrossRef]
- Yamaguchi, T.; Fushida, S.; Yamamoto, Y.; Tsukada, T.; Kinoshita, J.; Oyama, K.; Miyashita, T.; Tajima, H.; Ninomiya, I.; Munesue, S.; et al. Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination. Gastric Cancer 2016, 19, 1052–1065. [Google Scholar] [CrossRef]
- Principe, N.; Kidman, J.; Lake, R.A.; Lesterhuis, W.J.; Nowak, A.K.; McDonnell, A.M.; Chee, J. Malignant Pleural Effusions—A Window Into Local Anti-Tumor T Cell Immunity? Front. Oncol. 2021, 11, 672747. [Google Scholar] [CrossRef]
- Wang, F.; Yang, L.; Gao, Q.; Huang, L.; Wang, L.; Wang, J.; Wang, S.; Zhang, B.; Zhang, Y. CD163+CD14+ macrophages, a potential immune biomarker for malignant pleural effusion. Cancer Immunol. Immunother. 2015, 64, 965–976. [Google Scholar] [CrossRef]
- Liu, C.-Y.; Xu, J.-Y.; Shi, X.-Y.; Huang, W.; Ruan, T.-Y.; Xie, P.; Ding, J.-L. M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab. Investig. 2013, 93, 844–854. [Google Scholar] [CrossRef] [PubMed]
- Jie, X.-X.; Zhang, X.-Y.; Xu, C.-J. Epithelial-to-mesenchymal transition, circulating tumor cells and cancer metastasis: Mechanisms and clinical applications. Oncotarget 2017, 8, 81558–81571. [Google Scholar] [CrossRef] [PubMed]
- Song, K.-A.; Faber, A.C. Epithelial-to-mesenchymal transition and drug resistance: Transitioning away from death. J. Thorac. Dis. 2019, 11, E82–E85. [Google Scholar] [CrossRef]
- Szabo, P.M.; Vajdi, A.; Kumar, N.; Tolstorukov, M.Y.; Chen, B.J.; Edwards, R.; Ligon, K.L.; Chasalow, S.D.; Chow, K.-H.; Shetty, A.; et al. Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment. Sci. Rep. 2023, 13, 3051. [Google Scholar] [CrossRef]
- Mulet, M.; Osuna-Gomez, R.; Zamora, C.; Porcel, J.M.; Nieto, J.C.; Perea, L.; Pajares, V.; Muñoz-Fernandez, A.M.; Calvo, N.; Sorolla, M.A.; et al. Influence of Malignant Pleural Fluid from Lung Adenocarcinoma Patients on Neutrophil Response. Cancers 2022, 14, 2529. [Google Scholar] [CrossRef] [PubMed]
- Gabrilovich, D.I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 2017, 5, 3. [Google Scholar] [CrossRef]
- Nair, R.; Somasundaram, V.; Kuriakose, A.; Krishn, S.R.; Raben, D.; Salazar, R.; Nair, P. Deciphering T-cell exhaustion in the tumor microenvironment: Paving the way for innovative solid tumor therapies. Front. Immunol. 2025, 16, 1548234. [Google Scholar] [CrossRef]
- Sen, D.R.; Kaminski, J.; Barnitz, R.A.; Kurachi, M.; Gerdemann, U.; Yates, K.B.; Tsao, H.W.; Godec, J.; LaFleur, M.W.; Brown, F.D.; et al. The epigenetic landscape of T cell exhaustion. Science 2016, 354, 1165–1169. [Google Scholar] [CrossRef] [PubMed]
- Wherry, E.J.; Ha, S.-J.; Kaech, S.M.; Haining, W.N.; Sarkar, S.; Kalia, V.; Subramaniam, S.; Blattman, J.N.; Barber, D.L.; Ahmed, R. Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection. Immunity 2007, 27, 670–684. [Google Scholar] [CrossRef]
- van der Heide, V.; Humblin, E.; Vaidya, A.; Kamphorst, A.O. Advancing beyond the twists and turns of T cell exhaustion in cancer. Sci. Transl. Med. 2022, 14, eabo4997. [Google Scholar] [CrossRef]
- Doering Travis, A.; Crawford, A.; Angelosanto Jill, M.; Paley Michael, A.; Ziegler Carly, G.; Wherry, E.J. Network Analysis Reveals Centrally Connected Genes and Pathways Involved in CD8+ T Cell Exhaustion versus Memory. Immunity 2012, 37, 1130–1144. [Google Scholar] [CrossRef] [PubMed]
- Pearce, E.L. Metabolism in T cell activation and differentiation. Curr. Opin. Immunol. 2010, 22, 314–320. [Google Scholar] [CrossRef]
- Chapman, N.M.; Boothby, M.R.; Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 2020, 20, 55–70. [Google Scholar] [CrossRef]
- Sprent, J.; Surh, C.D. Normal T cell homeostasis: The conversion of naive cells into memory-phenotype cells. Nat. Immunol. 2011, 12, 478–484. [Google Scholar] [CrossRef] [PubMed]
- Hamilton, S.E.; Jameson, S.C. CD8 T cell quiescence revisited. Trends Immunol. 2012, 33, 224–230. [Google Scholar] [CrossRef] [PubMed]
- Allam, A.; Conze, D.B.; Giardino Torchia, M.L.; Munitic, I.; Yagita, H.; Sowell, R.T.; Marzo, A.L.; Ashwell, J.D. The CD8+ memory T-cell state of readiness is actively maintained and reversible. Blood 2009, 114, 2121–2130. [Google Scholar] [CrossRef]
- De Silva, P.; Garaud, S.; Solinas, C.; de Wind, A.; Van den Eyden, G.; Jose, V.; Gu-Trantien, C.; Migliori, E.; Boisson, A.; Naveaux, C.; et al. FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer. EBioMedicine 2019, 39, 226–238. [Google Scholar] [CrossRef]
- Tu, E.; Chia, C.P.Z.; Chen, W.; Zhang, D.; Park, S.A.; Jin, W.; Wang, D.; Alegre, M.-L.; Zhang, Y.E.; Sun, L.; et al. T Cell Receptor-Regulated TGF-beta Type I Receptor Expression Determines T Cell Quiescence and Activation. Immunity 2018, 48, 745–759.e6. [Google Scholar] [CrossRef]
- Donnenberg, V.S.; Luketich, J.D.; Popov, B.; Bartlett, D.L.; Donnenberg, A.D. A common secretomic signature across epithelial cancers metastatic to the pleura supports IL-6 axis therapeutic targeting. Front. Immunol. 2024, 15, 1404373. [Google Scholar] [CrossRef]
- Wagner, P.L.; Knotts, C.M.; Donnenberg, V.S.; Dadgar, N.; Cruz Pico, C.X.; Xiao, K.; Zaidi, A.; Schifman, S.C.; Allen, C.J.; Donnenberg, A.D.; et al. Characterizing the Immune Environment in Peritoneal Carcinomatosis: Insights for Novel Immunotherapy Strategies. Ann. Surg. Oncol. 2024, 31, 2069–2077. [Google Scholar] [CrossRef]
- Hu, C.Y.; Zhang, Y.H.; Wang, T.; Chen, L.; Gong, Z.H.; Wan, Y.S.; Li, Q.J.; Li, Y.S.; Zhu, B. Interleukin-2 reverses CD8+ T cell exhaustion in clinical malignant pleural effusion of lung cancer. Clin. Exp. Immunol. 2016, 186, 106–114. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.; Wei, Y.; Yang, W.; Huang, Q.; Chen, Y.; Zeng, K.; Chen, J. IL-6: The Link Between Inflammation, Immunity and Breast Cancer. Front. Oncol. 2022, 12, 903800. [Google Scholar] [CrossRef]
- Donnenberg, A.D.; Luketich, J.D.; Dhupar, R.; Donnenberg, V.S. Treatment of malignant pleural effusions: The case for localized immunotherapy. J. Immunother. Cancer 2019, 7, 110. [Google Scholar] [CrossRef] [PubMed]
- Heikkilä, K.; Ebrahim, S.; Lawlor, D.A. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur. J. Cancer 2008, 44, 937–945. [Google Scholar] [CrossRef]
- Lippitz, B.E. Cytokine patterns in patients with cancer: A systematic review. Lancet Oncol. 2013, 14, e218–e228. [Google Scholar] [CrossRef]
- Shkhyan, R.; Flynn, C.; Lamoure, E.; Sarkar, A.; Van Handel, B.; Li, J.; York, J.; Banks, N.; Van der Horst, R.; Liu, N.Q.; et al. Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis. Sci. Transl. Med. 2023, 15, eabq2395. [Google Scholar] [CrossRef]
- Steensberg, A.; Fischer, C.P.; Keller, C.; Møller, K.; Pedersen, B.K. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am. J. Physiol.-Endocrinol. Metabolism. 2003, 285, E433–E437. [Google Scholar] [CrossRef]
- Wertel, I.; Suszczyk, D.; Pawłowska, A.; Bilska, M.; Chudzik, A.; Skiba, W.; Paduch, R.; Kotarski, J. Prognostic and Clinical Value of Interleukin 6 and CD45+CD14+ Inflammatory Cells with PD-L1+/PD-L2+ Expression in Patients with Different Manifestation of Ovarian Cancer. J. Immunol. Res. 2020, 2020, 1715064. [Google Scholar] [CrossRef]
- Sato, T.; Terai, M.; Tamura, Y.; Alexeev, V.; Mastrangelo, M.J.; Selvan, S.R. Interleukin 10 in the tumor microenvironment: A target for anticancer immunotherapy. Immunol. Res. 2011, 51, 170–182. [Google Scholar] [CrossRef] [PubMed]
- Mannino, M.H.; Zhu, Z.; Xiao, H.; Bai, Q.; Wakefield, M.R.; Fang, Y. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 2015, 367, 103–107. [Google Scholar] [CrossRef]
- Dennis, K.L.; Blatner, N.R.; Gounari, F.; Khazaie, K. Current status of IL-10 and regulatory T-cells in cancer. Curr. Opin. Oncol. 2013, 25, 637. [Google Scholar] [CrossRef]
- Iyer, S.S.; Cheng, G. Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease. Crit. Rev.™ Immunol. 2012, 32, 23–63. [Google Scholar] [CrossRef] [PubMed]
- Nixon, B.G.; Gao, S.; Wang, X.; Li, M.O. TGFβ control of immune responses in cancer: A holistic immuno-oncology perspective. Nat. Rev. Immunol. 2023, 23, 346–362. [Google Scholar] [CrossRef]
- Batlle, E.; Massagué, J. Transforming Grown Factor-β Signaling in Immunity and Cancer. Immunity 2019, 50, 924–940. [Google Scholar] [CrossRef]
- Xu, J.; Lamouille, S.; Derynck, R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 2009, 19, 156–172. [Google Scholar] [CrossRef]
- Stockhammer, P.; Ploenes, T.; Theegarten, D.; Schuler, M.; Maier, S.; Aigner, C.; Hegedus, B. Detection of TGF-β in pleural effusions for diagnosis and prognostic stratification of malignant pleural mesothelioma. Lung Cancer 2020, 139, 124–132. [Google Scholar] [CrossRef]
- Jain, A.; Song, R.; Wakeland, E.K.; Pasare, C. T cell-intrinsic IL-1R signaling licenses effector cytokine production by memory CD4 T cells. Nat. Commun. 2018, 9, 3185. [Google Scholar] [CrossRef] [PubMed]
- Togashi, Y.; Shitara, K.; Nishikawa, H. Regulatory T cells in cancer immunosuppression—Implications for anticancer therapy. Nat. Rev. Clin. Oncol. 2019, 16, 356–371. [Google Scholar] [CrossRef]
- Budna, J.; Spychalski, Ł.; Kaczmarek, M.; Frydrychowicz, M.; Goździk-Spychalska, J.; Batura-Gabryel, H.; Sikora, J. Regulatory T cells in malignant pleural effusions subsequent to lung carcinoma and their impact on the course of the disease. Immunobiology 2017, 222, 499–505. [Google Scholar] [CrossRef] [PubMed]
- Landskron, J.; Helland, Ø.; Torgersen, K.M.; Aandahl, E.M.; Gjertsen, B.T.; Bjørge, L.; Taskén, K. Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol. Immunother. CII 2014, 64, 337. [Google Scholar] [CrossRef]
- Nowatzky, J.; Stagnar, C.; Manches, O. OMIP-053: Identification, Classification, and Isolation of Major FoxP3 Expressing Human CD4(+) Treg Subsets. Cytom. A 2019, 95, 264–267. [Google Scholar] [CrossRef] [PubMed]
- Glass, M.C.; Glass, D.R.; Oliveria, J.P.; Mbiribindi, B.; Esquivel, C.O.; Krams, S.M.; Bendall, S.C.; Martinez, O.M. Human IL-10-producing B cells have diverse states that are induced from multiple B cell subsets. Cell Rep. 2022, 39, 110728. [Google Scholar] [CrossRef]
- Takahashi, K.; Kurashina, K.; Yamaguchi, H.; Kanamaru, R.; Ohzawa, H.; Miyato, H.; Saito, S.; Hosoya, Y.; Lefor, A.K.; Sata, N.; et al. Altered intraperitoneal immune microenvironment in patients with peritoneal metastases from gastric cancer. Front. Immunol. 2022, 13, 969468. [Google Scholar] [CrossRef]
- Popowicz, N.; Cheah, H.M.; Gregory, C.; Miranda, A.; Dick, I.M.; Lee, Y.C.G.; Creaney, J. Neutrophil-to-lymphocyte ratio in malignant pleural fluid: Prognostic significance. PLoS ONE 2021, 16, e0250628. [Google Scholar] [CrossRef]
- Ge, S.; Zhao, Y.; Liang, J.; He, Z.; Li, K.; Zhang, G.; Hua, B.; Zheng, H.; Guo, Q.; Qi, R.; et al. Immune modulation in malignant pleural effusion: From microenvironment to therapeutic implications. Cancer Cell Int. 2024, 24, 105. [Google Scholar] [CrossRef]
- Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 2012, 12, 253–268. [Google Scholar] [CrossRef] [PubMed]
- Tobin, R.P.; Jordan, K.R.; Kapoor, P.; Spongberg, E.; Davis, D.; Vorwald, V.M.; Couts, K.L.; Gao, D.; Smith, D.E.; Borgers, J.S.W.; et al. IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients. Front. Oncol. 2019, 9, 1223. [Google Scholar] [CrossRef]
- Sugita, Y.; Yamashita, K.; Fujita, M.; Saito, M.; Yamada, K.; Agawa, K.; Watanabe, A.; Fukuoka, E.; Hasegawa, H.; Kanaji, S.; et al. CD244+ polymorphonuclear myeloid-derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model. Oncol. Rep. 2021, 45, 106. [Google Scholar] [CrossRef]
- Werb, Z.; Lu, P. The Role of Stroma in Tumor Development. Cancer J. 2015, 21, 250–253. [Google Scholar] [CrossRef] [PubMed]
- Connolly, J.L.; Schnitt, S.J.; Wang, H.H.; Longtine, J.A.; Dvorak, A.; Dvorak, H.F. Tumor Structure and Tumor Stroma Generation. In Holland-Frei Cancer Medicine, 6th ed.; BC Decker: London, UK, 2003. [Google Scholar]
- Karpathiou, G.; Péoc’h, M.; Sundaralingam, A.; Rahman, N.; Froudarakis, M.E. Inflammation of the Pleural Cavity: A Review on Pathogenesis, Diagnosis and Implications in Tumor Pathophysiology. Cancers 2022, 14, 1415. [Google Scholar] [CrossRef] [PubMed]
- Markov, A.G.; Voronkova, M.A.; Volgin, G.N.; Yablonsky, P.K.; Fromm, M.; Amasheh, S. Tight junction proteins contribute to barrier properties in human pleura. Respir. Physiol. Neurobiol. 2011, 175, 331–335. [Google Scholar] [CrossRef]
- Rakina, M.; Kazakova, A.; Villert, A.; Kolomiets, L.; Larionova, I. Spheroid Formation and Peritoneal Metastasis in Ovarian Cancer: The Role of Stromal and Immune Components. Int. J. Mol. Sci. 2022, 23, 6215. [Google Scholar] [CrossRef]
- Rynne-Vidal, A.; Jiménez-Heffernan, J.A.; Fernández-Chacón, C.; López-Cabrera, M.; Sandoval, P. The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis. Cancers 2015, 7, 1994–2011. [Google Scholar] [CrossRef] [PubMed]
- Lu, H.; Clauser, K.R.; Tam, W.L.; Frose, J.; Ye, X.; Eaton, E.N.; Reinhardt, F.; Donnenberg, V.S.; Bhargava, R.; Carr, S.A.; et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat. Cell Biol. 2014, 16, 1105–1117. [Google Scholar] [CrossRef] [PubMed]
- Yin, T.; Wang, G.; He, S.; Shen, G.; Su, C.; Zhang, Y.; Wei, X.; Ye, T.; Li, L.; Yang, S.; et al. Malignant Pleural Effusion and ascites Induce Epithelial-Mesenchymal Transition and Cancer Stem-like Cell Properties via the Vascular Endothelial Growth Factor (VEGF)/Phosphatidylinositol 3-Kinase (PI3K)/Akt/Mechanistic Target of Rapamycin (mTOR) Pathway. J. Biol. Chem. 2016, 291, 26750–26761. [Google Scholar] [CrossRef]
- Miao, Z.-F.; Zhao, T.-T.; Wang, Z.-N.; Miao, F.; Xu, Y.-Y.; Mao, X.-Y.; Gao, J.; Wu, J.-H.; Liu, X.-Y.; You, Y.; et al. Transforming growth factor-beta1 signaling blockade attenuates gastric cancer cell-induced peritoneal mesothelial cell fibrosis and alleviates peritoneal dissemination both in vitro and in vivo. Tumour Biol. 2014, 35, 3575–3583. [Google Scholar] [CrossRef]
- Ito, M.; Nakano, M.; Ariyama, H.; Yamaguchi, K.; Tanaka, R.; Semba, Y.; Sugio, T.; Miyawaki, K.; Kikushige, Y.; Mizuno, S.; et al. Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions. Cancer Lett. 2022, 532, 215597. [Google Scholar] [CrossRef]
- Lorenc, E.; Varinelli, L.; Chighizola, M.; Brich, S.; Pisati, F.; Guaglio, M.; Baratti, D.; Deraco, M.; Gariboldi, M.; Podestà, A. Correlation between biological and mechanical properties of extracellular matrix from colorectal peritoneal metastases in human tissues. Sci. Rep. 2023, 13, 12175. [Google Scholar] [CrossRef]
- Berek, J.S.; Hacker, N.F.; Lichtenstein, A.; Jung, T.; Spina, C.; Knox, R.M.; Brady, J.; Greene, T.; Ettinger, L.M.; Lagasse, L.D.; et al. Intraperitoneal recombinant alpha-interferon for “salvage” immunotherapy in stage III epithelial ovarian cancer: A Gynecologic Oncology Group Study. Cancer Res. 1985, 45, 4447–4453. [Google Scholar]
- Toge, T.; Yamada, H.; Aratani, K.; Kameda, A.; Kuroi, K.; Hisamatsu, K.; Hattori, T. Effects of intraperitoneal administration of OK-432 for patients with advanced cancer. Jpn. J. Surg. 1985, 15, 260–265. [Google Scholar] [CrossRef]
- Knisely, A.; Hinchcliff, E.; Fellman, B.; Mosley, A.; Lito, K.; Hull, S.; Westin, S.N.; Sood, A.K.; Schmeler, K.M.; Taylor, J.S.; et al. Phase 1b study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis. Med 2024, 5, 311–320.e3. [Google Scholar] [CrossRef]
- Hamanishi, J.; Mandai, M.; Ikeda, T.; Minami, M.; Kawaguchi, A.; Murayama, T.; Kanai, M.; Mori, Y.; Matsumoto, S.; Chikuma, S.; et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J. Clin. Oncol. 2015, 33, 4015–4022. [Google Scholar] [CrossRef] [PubMed]
- Kang, Y.-K.; Boku, N.; Satoh, T.; Ryu, M.-H.; Chao, Y.; Kato, K.; Chung, H.C.; Chen, J.-S.; Muro, K.; Kang, W.K.; et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017, 390, 2461–2471. [Google Scholar] [CrossRef]
- Zhang, L.; Mai, W.; Jiang, W.; Geng, Q. Sintilimab: A Promising Anti-Tumor PD-1 Antibody. Front. Oncol. 2020, 10, 594558. [Google Scholar] [CrossRef]
- Lv, T.; Wu, G.; Song, X.; Li, X.; Zhang, J.; Song, Y. P16.05 Exploratory Study of Sintilimab Intrapleural Therapy for NSCLC-Mediated Malignant Pleural Effusion. J. Thorac. Oncol. 2021, 16, S349–S350. [Google Scholar] [CrossRef]
- Tsimafeyeu, I.; Goutnik, V.; Shrainer, I.; Kosyrev, V.; Bondarenko, A.; Utyashev, I. Multicenter phase 2 study of intrapleural nivolumab in patients with metastatic non-small cell lung cancer and pleural effusion. Am. J. Cancer Res. 2023, 13, 1103–1106. [Google Scholar]
- Tsimafeyeu, I.; Goutnik, V.; Shrainer, I.; Kosyrev, V.; Bondarenko, A.; Utyashev, I. Intrapleural nivolumab in cancer patients with pleural effusion. J. Cancer Res. Ther. 2024, 20, 1036–1038. [Google Scholar] [CrossRef]
- Hossen, M.M.; Ma, Y.; Yin, Z.; Xia, Y.; Du, J.; Huang, J.Y.; Huang, J.J.; Zou, L.; Ye, Z.; Huang, Z. Current understanding of CTLA-4: From mechanism to autoimmune diseases. Front. Immunol. 2023, 14, 1198365. [Google Scholar] [CrossRef] [PubMed]
- Zhao, Y.; Yang, W.; Huang, Y.; Cui, R.; Li, X.; Li, B. Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy. Cell. Physiol. Biochem. 2018, 47, 721–734. [Google Scholar] [CrossRef] [PubMed]
- Kooshkaki, O.; Derakhshani, A.; Hosseinkhani, N.; Torabi, M.; Safaei, S.; Brunetti, O.; Racanelli, V.; Silvestris, N.; Baradaran, B. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials. Int. J. Mol. Sci. 2020, 21, 4427. [Google Scholar] [CrossRef] [PubMed]
- Murthy, P.; Ekeke, C.N.; Russell, K.L.; Butler, S.C.; Wang, Y.; Luketich, J.D.; Soloff, A.C.; Dhupar, R.; Lotze, M.T. Making cold malignant pleural effusions hot: Driving novel immunotherapies. Oncoimmunology 2019, 8, e1554969. [Google Scholar] [CrossRef] [PubMed]
- Finley, S.D.; Popel, A.S. Effect of Tumor Microenvironment on Tumor VEGF During Anti-VEGF Treatment: Systems Biology Predictions. JNCI J. Natl. Cancer Inst. 2013, 105, 802–811. [Google Scholar] [CrossRef]
- Zebrowski, B.K.; Liu, W.; Ramirez, K.; Akagi, Y.; Mills, G.B.; Ellis, L.M. Markedly Elevated Levels of Vascular Endothelial Growth Factor in Malignant Ascites. Ann. Surg. Oncol. 1999, 6, 373–378. [Google Scholar] [CrossRef]
- Zeng, H.; Zhang, Y.; Tan, S.; Huang, Q.; Pu, X.; Tian, P.; Li, Y. Efficacy of bevacizumab through an indwelling pleural catheter in non-small cell lung cancer patients with symptomatic malignant pleural effusion. BMC Pulm. Med. 2024, 24, 89. [Google Scholar] [CrossRef]
- Razenberg, L.G.E.M.; van Gestel, Y.R.B.M.; Lemmens, V.E.P.P.; de Hingh, I.H.J.T.; Creemers, G.-J. Bevacizumab in Addition to Palliative Chemotherapy for Patients With Peritoneal Carcinomatosis of Colorectal Origin: A Nationwide Population-Based Study. Clin. Color. Cancer 2016, 15, e41–e46. [Google Scholar] [CrossRef]
- Sjoquist, K.M.; Espinoza, D.; Mileshkin, L.; Ananda, S.; Shannon, C.; Yip, S.; Goh, J.; Bowtell, D.; Harrison, M.; Friedlander, M.L. REZOLVE (ANZGOG-1101): A phase 2 trial of intraperitoneal bevacizumab to treat symptomatic ascites in patients with chemotherapy-resistant, epithelial ovarian cancer. Gynecol. Oncol. 2021, 161, 374–381. [Google Scholar] [CrossRef] [PubMed]
- Jordan, K.; Luetkens, T.; Gog, C.; Killing, B.; Arnold, D.; Hinke, A.; Stahl, M.; Freier, W.; Rüssel, J.; Atanackovic, D.; et al. Intraperitoneal bevacizumab for control of malignant ascites due to advanced-stage gastrointestinal cancers: A multicentre double-blind, placebo-controlled phase II study—AIO SUP-0108. Eur. J. Cancer 2016, 63, 127–134. [Google Scholar] [CrossRef] [PubMed]
- Ghasemi, K.; Ghasemi, K. Evaluation of the Tocilizumab therapy in human cancers: Latest evidence and clinical potential. J. Clin. Pharm. Ther. 2022, 47, 2360–2368. [Google Scholar] [CrossRef]
- Park, H.; Lewis, C.; Dadgar, N.; Sherry, C.; Evans, S.; Ziobert, S.; Omstead, A.; Zaidi, A.; Xiao, K.; Ghosh, S.; et al. Intra-pleural and intra-peritoneal tocilizumab therapy for managing malignant pleural effusions and ascites: The Regional Immuno-Oncology Trial (RIOT)—2 Study protocol. Surg. Oncol. Insight 2024, 1, 100045. [Google Scholar] [CrossRef]
- Sun, Y.; Yu, X.; Wang, X.; Yuan, K.; Wang, G.; Hu, L.; Zhang, G.; Pei, W.; Wang, L.; Sun, C.; et al. Bispecific antibodies in cancer therapy: Target selection and regulatory requirements. Acta Pharm. Sin. B 2023, 13, 3583–3597. [Google Scholar] [CrossRef]
- Knödler, M.; Körfer, J.; Kunzmann, V.; Trojan, J.; Daum, S.; Schenk, M.; Kullmann, F.; Schroll, S.; Behringer, D.; Stahl, M.; et al. Randomised phase II trial to investigate catumaxomab (anti-EpCAM × anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer. Br. J. Cancer 2018, 119, 296–302. [Google Scholar] [CrossRef] [PubMed]
- Burges, A.; Wimberger, P.; Kümper, C.; Gorbounova, V.; Sommer, H.; Schmalfeldt, B.; Pfisterer, J.; Lichinitser, M.; Makhson, A.; Moiseyenko, V.; et al. Effective Relief of Malignant Ascites in Patients with Advanced Ovarian Cancer by a Trifunctional Anti-EpCAM × Anti-CD3 Antibody: A Phase I/II Study. Clin. Cancer Res. 2007, 13, 3899–3905. [Google Scholar] [CrossRef]
- Heiss, M.M.; Murawa, P.; Koralewski, P.; Kutarska, E.; Kolesnik, O.O.; Ivanchenko, V.V.; Dudnichenko, A.S.; Aleknaviciene, B.; Razbadauskas, A.; Gore, M.; et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int. J. Cancer 2010, 127, 2209–2221. [Google Scholar] [CrossRef]
- Sebastian, M.; Jaeger, M.; Kiewe, P.; Schuette, W.; Wiewrodt, R.; Lindhofer, H.; Mueller, B.; Friccius-Quecke, H.; Quecke, H.F.; Schmittel, A. Effects of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) on proliferation and cytokine secretion of immune cells in malignant pleural effusion. J. Clin. Oncol. 2007, 25 (Suppl. S18), 3046. [Google Scholar] [CrossRef]
- Liu, R.; Xu, J.; Lin, R.; Li, N.; Li, G.; Zhang, T.; Zhao, J.; Li, J.; Sun, M.; Wang, K.; et al. Updated results of a phase II trial evaluating an anti-EpCAM × anti-CD3 bispecific antibody, M701, for the treatment of malignant ascites. Ann. Oncol. 2024, 35, S1427–S1428. [Google Scholar] [CrossRef]
- Cai, J.; Zhang, F.; Song, Z.; Jin, J.; Lv, D.; Pang, W.; Yi, T.; Wang, G.; Yao, J.; Wang, B.; et al. 1371P An anti-EpCAM × CD3 bispecific antibody, M701, for the treatment of malignant pleural effusion in NSCLC patients: Intermediate results of a prospective multicenter phase Ib trial. Ann. Oncol. 2024, 35, S862. [Google Scholar] [CrossRef]
- Santos Apolonio, J.; Lima de Souza Gonçalves, V.; Cordeiro Santos, M.L.; Silva Luz, M.; Silva Souza, J.V.; Rocha Pinheiro, S.L.; de Souza, W.R.; Sande Loureiro, M.; de Melo, F.F. Oncolytic virus therapy in cancer: A current review. World J. Virol. 2021, 10, 229–255. [Google Scholar] [CrossRef]
- Guo, Z.S.; Bartlett, D.L. Oncolytic viruses as platform for multimodal cancer therapeutics: A promising land. Cancer Gene Ther. 2014, 21, 261–263. [Google Scholar] [CrossRef]
- Lin, D.; Shen, Y.; Liang, T. Oncolytic virotherapy: Basic principles, recent advances and future directions. Signal Transduct. Target. Ther. 2023, 8, 1–29. [Google Scholar] [CrossRef]
- McCart, J.A.; Ward, J.M.; Lee, J.; Hu, Y.; Alexander, H.R.; Libutti, S.K.; Moss, B.; Bartlett, D.L. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 2001, 61, 8751–8757. [Google Scholar]
- Ge, Y.; Wang, H.; Ren, J.; Liu, W.; Chen, L.; Chen, H.; Ye, J.; Dai, E.; Ma, C.; Ju, S.; et al. Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety. J. Immunother. Cancer 2020, 8, e000710. [Google Scholar] [CrossRef]
- Downs-Canner, S.; Guo, Z.S.; Ravindranathan, R.; Breitbach, C.J.; O’Malley, M.E.; Jones, H.L.; Moon, A.; McCart, J.A.; Shuai, Y.; Zeh, H.J.; et al. Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers. Mol. Ther. 2016, 24, 1492–1501. [Google Scholar] [CrossRef]
- Gong, J.; Sachdev, E.; Mita, A.C.; Mita, M.M. Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity. World J. Methodol. 2016, 6, 25–42. [Google Scholar] [CrossRef]
- Ponce, S.; Cedres, S.; Ricordel, C.; Isambert, N.; Viteri, S.; Herrera-Juarez, M.; Martinez-Marti, A.; Navarro, A.; Lederlin, M.; Serres, X.; et al. ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: A randomized phase 2 study investigating clinical outcomes and the tumor microenvironment. J. Immunother. Cancer 2023, 11, e007552. [Google Scholar] [CrossRef]
- Wong, M.K.; Milhem, M.M.; Sacco, J.J.; Michels, J.; In, G.K.; Munoz Couselo, E.; Schadendorf, D.; Beasley, G.M.; Niu, J.; Chmielowski, B.; et al. RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE). J. Clin. Oncol. 2025, JCO2501346. [Google Scholar] [CrossRef]
- Lauer, U.M.; Schell, M.; Beil, J.; Berchtold, S.; Koppenhöfer, U.; Glatzle, J.; Königsrainer, A.; Möhle, R.; Nann, D.; Fend, F.; et al. Phase I Study of Oncolytic Vaccinia Virus GL-ONC1 in Patients with Peritoneal Carcinomatosis. Clin. Cancer Res. 2018, 24, 4388–4398. [Google Scholar] [CrossRef]
- Weibel, S.; Hofmann, E.; Basse-Luesebrink, T.C.; Donat, U.; Seubert, C.; Adelfinger, M.; Gnamlin, P.; Kober, C.; Frentzen, A.; Gentschev, I.; et al. Treatment of malignant effusion by oncolytic virotherapy in an experimental subcutaneous xenograft model of lung cancer. J. Transl. Med. 2013, 11, 106. [Google Scholar] [CrossRef]
- Giehl, E.; Kosaka, H.; Liu, Z.; Feist, M.; Kammula, U.S.; Lotze, M.T.; Ma, C.; Guo, Z.S.; Bartlett, D.L. In Vivo Priming of Peritoneal Tumor-Reactive Lymphocytes with a Potent Oncolytic Virus for Adoptive Cell Therapy. Front. Immunol. 2021, 12, 610042. [Google Scholar] [CrossRef] [PubMed]
- Lee, Y.S.; Lee, W.S.; Kim, C.W.; Lee, S.J.; Yang, H.; Kong, S.J.; Ning, J.; Yang, K.M.; Kang, B.; Kim, W.R.; et al. Oncolytic vaccinia virus reinvigorates peritoneal immunity and cooperates with immune checkpoint inhibitor to suppress peritoneal carcinomatosis in colon cancer. J. Immunother. Cancer 2020, 8, e000857. [Google Scholar] [CrossRef]
- Chee, J.; Watson, M.W.; Chopra, A.; Nguyen, B.; Cook, A.M.; Creaney, J.; Lesterhuis, W.J.; Robinson, B.W.; Lee, Y.C.G.; Nowak, A.K.; et al. Tumour associated lymphocytes in the pleural effusions of patients with mesothelioma express high levels of inhibitory receptors. BMC Res. Notes 2018, 11, 864. [Google Scholar] [CrossRef] [PubMed]
- Yossef, R.; Tran, E.; Deniger, D.C.; Gros, A.; Pasetto, A.; Parkhurst, M.R.; Gartner, J.J.; Prickett, T.D.; Cafri, G.; Robbins, P.F.; et al. Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy. JCI Insight 2018, 3, e122467. [Google Scholar] [CrossRef]
- Johnson, C.B.; May, B.R.; Riesenberg, B.P.; Suriano, S.; Mehrotra, S.; Garrett-Mayer, E.; Salem, M.L.; Jeng, E.K.; Wong, H.C.; Paulos, C.M.; et al. Enhanced Lymphodepletion Is Insufficient to Replace Exogenous IL2 or IL15 Therapy in Augmenting the Efficacy of Adoptively Transferred Effector CD8+ T Cells. Cancer Res. 2018, 78, 3067–3074. [Google Scholar] [CrossRef] [PubMed]
- Freedman, R.S.; Edwards, C.L.; Kavanagh, J.J.; Kudelka, A.P.; Katz, R.L.; Carrasco, C.H.; Atkinson, E.N.; Scott, W.; Tomasovic, B.; Templin, S.; et al. Intraperitoneal Adoptive Immunotherapy of Ovarian Carcinoma with Tumor-Infiltrating Lymphocytes and Low-Dose Recombinant Interleukin-2: A Pilot Trial. J. Immunother. 1994, 16, 198. [Google Scholar] [CrossRef]
- Betof Warner, A.; Hamid, O.; Komanduri, K.; Amaria, R.; Butler, M.O.; Haanen, J.; Nikiforow, S.; Puzanov, I.; Sarnaik, A.; Bishop, M.R.; et al. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J. Immunother. Cancer. 2024, 12, e008735. [Google Scholar] [CrossRef]
- Zacharakis, N.; Huq, L.M.; Seitter, S.J.; Kim, S.P.; Gartner, J.J.; Sindiri, S.; Hill, V.K.; Li, Y.F.; Paria, B.C.; Ray, S.; et al. Breast Cancers Are Immunogenic: Immunologic Analyses and a Phase II Pilot Clinical Trial Using Mutation-Reactive Autologous Lymphocytes. J. Clin. Oncol. 2022, 40, 1741–1754. [Google Scholar] [CrossRef]
- Paijens, S.T.; Vledder, A.; de Bruyn, M.; Nijman, H.W. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell. Mol. Immunol. 2021, 18, 842–859. [Google Scholar] [CrossRef]
- L’Orphelin, J.M.; Lancien, U.; Nguyen, J.M.; Coronilla, F.J.S.; Saiagh, S.; Cassecuel, J.; Boussemart, L.; Dompmartin, A.; Dréno, B. NIVO-TIL: Combination anti-PD-1 therapy and adoptive T-cell transfer in untreated metastatic melanoma: An exploratory open-label phase I trial. Acta Oncol. 2024, 63, 867–877. [Google Scholar] [CrossRef]
- Marofi, F.; Motavalli, R.; Safonov, V.A.; Thangavelu, L.; Yumashev, A.V.; Alexander, M.; Shomali, N.; Chartrand, M.S.; Pathak, Y.; Jarahian, M.; et al. CAR T cells in solid tumors: Challenges and opportunities. Stem Cell Res. Ther. 2021, 12, 81. [Google Scholar] [CrossRef]
- Park, J.H.; Geyer, M.B.; Brentjens, R.J. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: Interpreting clinical outcomes to date. Blood 2016, 127, 3312–3320. [Google Scholar] [CrossRef] [PubMed]
- Adusumilli, P.S.; Zauderer, M.G.; Rivière, I.; Solomon, S.B.; Rusch, V.W.; O’Cearbhaill, R.E.; Zhu, A.; Cheema, W.; Chintala, N.K.; Halton, E.; et al. A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab. Cancer Discov. 2021, 11, 2748–2763. [Google Scholar] [CrossRef] [PubMed]
- Bagley, S.J.; Logun, M.; Fraietta, J.A.; Wang, X.; Desai, A.S.; Bagley, L.J.; Nabavizadeh, A.; Jarocha, D.; Martins, R.; Maloney, E.; et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Ralpha2 in recurrent glioblastoma: Phase 1 trial interim results. Nat. Med. 2024, 30, 1320–1329. [Google Scholar] [CrossRef] [PubMed]
- Morello, A.; Sadelain, M.; Adusumilli, P.S. Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discov. 2016, 6, 133–146. [Google Scholar] [CrossRef]
- Dobersberger, M.; Sumesgutner, D.; Zajc, C.U.; Salzer, B.; Laurent, E.; Emminger, D.; Sylvander, E.; Lehner, E.; Teufl, M.; Seigner, J.; et al. An engineering strategy to target activated EGFR with CAR T cells. Cell Rep. Methods 2024, 4, 100728. [Google Scholar] [CrossRef]
- Katz, S.C.; Point, G.R.; Cunetta, M.; Thorn, M.; Guha, P.; Espat, N.J.; Boutros, C.; Hanna, N.; Junghans, R.P. Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery. Cancer Gene Ther. 2016, 23, 142–148. [Google Scholar] [CrossRef] [PubMed]
- Murad, J.P.; Kozlowska, A.K.; Lee, H.J.; Ramamurthy, M.; Chang, W.-C.; Yazaki, P.; Colcher, D.; Shively, J.; Cristea, M.; Forman, S.J.; et al. Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells. Front. Immunol. 2018, 9, 2268. [Google Scholar] [CrossRef]
- Aujayeb, A.; Astoul, P. A Diagnostic Approach to Malignant Pleural Mesothelioma. Pulm. Ther. 2025, 11, 503–517. [Google Scholar] [CrossRef] [PubMed]
- Chintala, N.K.; Restle, D.; Quach, H.; Saini, J.; Bellis, R.; Offin, M.; Beattie, J.; Adusumilli, P.S. CAR T-cell therapy for pleural mesothelioma: Rationale, preclinical development, and clinical trials. Lung Cancer 2021, 157, 48–59. [Google Scholar] [CrossRef]
- Frey, N.; Porter, D. Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biol. Blood Marrow Transplant. 2019, 25, e123–e127. [Google Scholar] [CrossRef]
- Chen, F.; Teachey, D.T.; Pequignot, E.; Frey, N.; Porter, D.; Maude, S.L.; Grupp, S.A.; June, C.H.; Melenhorst, J.J.; Lacey, S.F. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J. Immunol. Methods 2016, 434, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Ma, N.; Okamoto, S.; Amaishi, Y.; Sato, E.; Seo, N.; Mineno, J.; Takesako, K.; Kato, T.; Shiku, H. Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome. Oncoimmunology 2016, 5, e1211218. [Google Scholar] [CrossRef]
- Yang, Y.; Vedvyas, Y.; Alcaina, Y.; Trumper, S.J.; Babu, D.S.; Min, I.M.; Tremblay, J.M.; Shoemaker, C.B.; Jin, M.M. Affinity-tuned mesothelin CAR T cells demonstrate enhanced targeting specificity and reduced off-tumor toxicity. JCI Insight 2024, 9, e186268. [Google Scholar] [CrossRef]
- Donnenberg, V.S.; Lister, J.; Briedenbaugh, C.L.; Wagner, P.; Bartlett, D.; Donnenberg, A.D. Fast TIL: Rapid Manufacture of an Adoptive Cellular Therapeutic from Pleural Infiltrating T cells for Intrapleural Administration. Cytotherapy 2025, in press. [Google Scholar] [CrossRef]
- Chu, H.; Du, F.; Gong, Z.; Lian, P.; Wang, Z.; Li, P.; Hu, B.; Chi, C.; Chen, J. Better Clinical Efficiency of TILs for Malignant Pleural Effusion and Ascites than Cisplatin Through Intrapleural and Intraperitoneal Infusion. Anticancer. Res. 2017, 37, 4587–4591. [Google Scholar] [CrossRef]
Identifier | Cavitary Environment | Investigational Treatment | Target | Trial Phase | Study Location |
---|---|---|---|---|---|
NCT06740019 | MPE | JMKX000197 | STING (Endoplasmic Reticulum IFN stimulator) | I | Beijing, China |
NCT05268172 | MPE, MA | T Cells in combination with IFNγ | ICAM-1, PD-L1, PD-1 | I | Wuxi, Jiangsu, China |
NCT06016179 | MPE, MA | Tocilizumab | IL-6Rα | I | Pittsburgh, PA, United States |
NCT05477927 | MPE, MA | Dual-targeting VEGFR1/PD-L1 CAR-T | VEGFR1, PD-L1 | I | Chengdu, Sichuan, China |
NCT06726564 | MPE | MT027 | B7H3 | I | Beijing, China |
NCT07090525 | MPE | Bevacizumab | VEGF | II | Qingdao, Shandong, China |
NCT04684459 | MPE, MA | Dual-targeting HER-2/PD-L1 CAR-T | HER2, PD-L1 | I | Chengdu, Sichuan, China |
NCT04919629 | MPE, MA | APL-2, Pembrolizumab, Bevacizumab | C3 Protein | II | Buffalo, NY, United States |
NCT06769295 | MPE | AK112 | PD-1, VEGF | II | Sichuan, Chengdu, China |
NCT05700656 | PC | Galunisertib | TGFβ | I, II | Amsterdam, The Netherlands |
NCT05801783 | PC | R130 | CD3 scFv/CD86/PD1/HSV2-US11 | I | Shanghai, China |
NCT03252938 | PC | IMP321 | PD-L1 | I | Germany |
NCT06623396 | PC | MSLN-targeted CAR-T | Mesothelin | I | New Jersey, United States |
NCT06433869 | MA | Bevacizumab, Serplulimab, rmhTNF-NC | VEGF, TNF, PD-1 | II | Guangzhou, China |
NCT06200376 | MA | T3011 | PD-1, IL-12 | I | Chengdu, Sichuan, China |
NCT06759064 | MA | Sintilimab | PD-1 | I, II | Jinan, Shandong, China |
NCT06046963 | PC, MA | Sintilimab | PD-1 | II | Hangzhou, Zhejiang, China |
NCT05438459 | MA | GAIA-102 | NK Cells | I, II | Fukuoka, Japan |
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Mirsky, P.O.; Wagner, P.L.; Mandic-Popov, M.; Donnenberg, V.S.; Donnenberg, A.D. The Tumor Environment in Peritoneal Carcinomatosis and Malignant Pleural Effusions: Implications for Therapy. Cancers 2025, 17, 3217. https://doi.org/10.3390/cancers17193217
Mirsky PO, Wagner PL, Mandic-Popov M, Donnenberg VS, Donnenberg AD. The Tumor Environment in Peritoneal Carcinomatosis and Malignant Pleural Effusions: Implications for Therapy. Cancers. 2025; 17(19):3217. https://doi.org/10.3390/cancers17193217
Chicago/Turabian StyleMirsky, Paige O., Patrick L. Wagner, Maja Mandic-Popov, Vera S. Donnenberg, and Albert D. Donnenberg. 2025. "The Tumor Environment in Peritoneal Carcinomatosis and Malignant Pleural Effusions: Implications for Therapy" Cancers 17, no. 19: 3217. https://doi.org/10.3390/cancers17193217
APA StyleMirsky, P. O., Wagner, P. L., Mandic-Popov, M., Donnenberg, V. S., & Donnenberg, A. D. (2025). The Tumor Environment in Peritoneal Carcinomatosis and Malignant Pleural Effusions: Implications for Therapy. Cancers, 17(19), 3217. https://doi.org/10.3390/cancers17193217