Cancer Immunology, Immunotherapy

, Volume 68, Issue 11, pp 1831–1838 | Cite as

The challenges of adoptive cell transfer in the treatment of human renal cell carcinoma

  • Zuzana Strizova
  • Jirina Bartunkova
  • Daniel SmrzEmail author
Focussed Research Review


Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Its incidence continues to rise worldwide with a rate of 2% per year. Approximately, one-third of the RCC patients are diagnosed at advanced stages due to the asymptomatic nature of its early stages. This represents a great hurdle, since RCC is largely chemoresistant/radioresistant, and targeted therapy of mRCC still has limited efficacy. The 5-year survival rate of metastatic RCC (mRCC) is only around 10%. Adoptive cell transfer (ACT), a particular form of cell-based anticancer immunotherapy, is a promising approach in the treatment of mRCC. The vaccination principle, however, faces unique challenges that preclude the efficacy of ACT. In this article, we review the main challenges of ACT in the treatment of mRCC and describe multiple methods that can be used to overcome these challenges. In this respect, the ultimate purpose of this review is to provide a descriptive tool by which to improve the development of novel protocols for ACT of mRCC.


Renal cell carcinoma ACT Tumor-infiltrating lymphocytes PECAM Peritumoral lymphocytes PIVAC 18 



Adoptive cell transfer


Clear cell RCC




Intratumoral fibrosis


Metastatic RCC

NK cell

Natural killer cell


Non-clear cell RCC


Peripheral blood mononuclear cell


Platelet endothelial cell adhesion molecule


Renal cell carcinoma


Tumor-infiltrating lymphocyte


TNF-related apoptosis-inducing ligand



We would like to thank Prof. Ilja Striz and Dr. Alasdair M. Gilfillan for a critical review of the manuscript.

Author contributions

Zuzana Strizova drafted and wrote the manuscript. Jirina Bartunkova contributed to the intellectual content and writing of the manuscript. Daniel Smrz contributed to the intellectual content and with Zuzana Strizova wrote the manuscript. All authors read and approved the final version of the manuscript.


Charles University—project GA UK No. 364218 and PRIMUS/MED/12 and funding by the Ministry of Health, Czech Republic—project AZV 16-28135A.

Compliance with ethical standards

Conflict of interest

The authors Zuzana Strizova and Daniel Smrz declare that there is no conflict of interest regarding this article. Jirina Bartunkova is a part-time employee and a minority shareholder of SOTIO, a.s., a biotech company developing cell-based immunotherapy.


  1. 1.
    Kabaria R, Klaassen Z, Terris MK (2016) Renal cell carcinoma: links and risks. Int J Nephrol Renovasc Dis 9:45–52PubMedPubMedCentralGoogle Scholar
  2. 2.
    Shea MW (2013) A proposal for a targeted screening program for renal cancer. Front Oncol 3:207CrossRefGoogle Scholar
  3. 3.
    Santoni M, Massari F, Di Nunno V, Conti A, Cimadamore A, Scarpelli M et al (2018) Immunotherapy in renal cell carcinoma: latest evidence and clinical implications. Drugs Context 7:212528CrossRefGoogle Scholar
  4. 4.
    Cohen JE, Merims S, Frank S, Engelstein R, Peretz T, Lotem M (2017) Adoptive cell therapy: past, present and future. Immunotherapy 9(2):183–196. CrossRefGoogle Scholar
  5. 5.
    Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348(6230):62–68CrossRefGoogle Scholar
  6. 6.
    Phan GQ, Rosenberg SA (2013) Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy. Cancer Control 20(4):289–297CrossRefGoogle Scholar
  7. 7.
    Tang X, Liu T, Zang X, Liu H, Wang D, Chen H et al (2013) Adoptive cellular immunotherapy in metastatic renal cell carcinoma: a systematic review and meta-analysis. PLoS ONE 8(5):e62847CrossRefGoogle Scholar
  8. 8.
    Kalos M, June CH (2013) Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39(1):49–60CrossRefGoogle Scholar
  9. 9.
    Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L et al (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16(9):2646–2655CrossRefGoogle Scholar
  10. 10.
    Bellone M, Calcinotto A, Corti A (2012) Won’t you come on in? How to favor lymphocyte infiltration in tumors. Oncoimmunology 1(6):986–988CrossRefGoogle Scholar
  11. 11.
    Torcellan T, Stolp J, Chtanova T (2017) In vivo imaging sheds light on immune cell migration and function in cancer. Front Immunol 8:309CrossRefGoogle Scholar
  12. 12.
    Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, Validire P, Trautmann A et al (2012) Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 122(3):899–910CrossRefGoogle Scholar
  13. 13.
    Bougherara H, Mansuet-Lupo A, Alifano M, Ngo C, Damotte D, Le Frere-Belda MA et al (2015) Real-time imaging of resident T cells in human lung and ovarian carcinomas reveals how different tumor microenvironments control T lymphocyte migration. Front Immunol 6:500CrossRefGoogle Scholar
  14. 14.
    Idorn M, Thor Straten P (2018) Chemokine receptors and exercise to tackle the inadequacy of T cell homing to the tumor site. Cells. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nayar S, Dasgupta P, Galustian C (2015) Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies—a review. Oncoimmunology 4(4):e1002720CrossRefGoogle Scholar
  16. 16.
    Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G (2011) Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res 71(17):5601–5605. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lee S, Margolin K (2012) Tumor-infiltrating lymphocytes in melanoma. Curr Oncol Rep 14(5):468–474CrossRefGoogle Scholar
  18. 18.
    Giraldo NA, Becht E, Pages F, Skliris G, Verkarre V, Vano Y, Mejean A, Saint-Aubert N, Lacroix L, Natario I, Lupo A, Alifano M, Damotte D, Cazes A, Triebel F, Freeman GJ, Dieu-Nosjean MC, Oudard S, Fridman WH, Sautes-Fridman C (2015) Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res 21(13):3031–3040. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Geissler K, Fornara P, Lautenschlager C, Holzhausen HJ, Seliger B, Riemann D (2015) Immune signature of tumor infiltrating immune cells in renal cancer. Oncoimmunology 4(1):e985082CrossRefGoogle Scholar
  20. 20.
    Strizova Z, Taborska P, Stakheev D, Partlova S, Havlova K, Vesely S, Bartunkova J, Smrz D (2019) NK and T cells with a cytotoxic/migratory phenotype accumulate in peritumoral tissue of patients with clear cell renal carcinoma. Urol Oncol 37(7):503–509. CrossRefGoogle Scholar
  21. 21.
    Crossey F, Marx S, Holters S, Schmitt K, Bohle RM, Schmidt T et al (2018) Robust method for isolation of tumor infiltrating lymphocytes with a high vital cell yield from small samples of renal cell carcinomas by a new collagenase-free mechanical procedure. Urol Oncol 36(9):402e1–402e10CrossRefGoogle Scholar
  22. 22.
    Mayor P, Starbuck K, Zsiros E (2018) Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies. Gynecol Oncol 150(2):361–369CrossRefGoogle Scholar
  23. 23.
    Voigt H, Kleeberg UR (1986) Malignes melanom. Springer, Berlin, p 185CrossRefGoogle Scholar
  24. 24.
    Cox TR, Erler JT (2016) Fibrosis and cancer: Partners in crime or opposing forces? Trends Cancer 2(6):279–282CrossRefGoogle Scholar
  25. 25.
    Joung JW, Oh HK, Lee SJ, Kim YA, Jung HJ (2018) Significance of intratumoral fibrosis in clear cell renal cell carcinoma. J Pathol Transl Med 52(5):323–330CrossRefGoogle Scholar
  26. 26.
    Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70:6171–6180. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Corti A, Pastorino F, Curnis F, Arap W, Ponzoni M, Pasqualini R (2012) Targeted drug delivery and penetration into solid tumors. Med Res Rev 32(5):1078–1091CrossRefGoogle Scholar
  28. 28.
    Gregorc V, Gaafar RM, Favaretto A, Grossi F, Jassem J, Polychronis A et al (2018) NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 19(6):799–811CrossRefGoogle Scholar
  29. 29.
    Zhang E, Xu H (2017) A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy. J Hematol Oncol 10(1):1CrossRefGoogle Scholar
  30. 30.
    Muller WA (2011) Mechanisms of leukocyte transendothelial migration. Annu Rev Pathol 6:323–344CrossRefGoogle Scholar
  31. 31.
    Berman ME, Xie Y, Muller WA (1996) Roles of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in natural killer cell transendothelial migration and beta 2 integrin activation. J Immunol 156(4):1515–1524Google Scholar
  32. 32.
    Dasgupta B, Dufour E, Mamdouh Z, Muller WA (2009) A novel and critical role for tyrosine 663 in platelet endothelial cell adhesion molecule-1 trafficking and transendothelial migration. J Immunol 182(8):5041–5051CrossRefGoogle Scholar
  33. 33.
    Andersen R, Westergaard MCW, Kjeldsen JW, Muller A, Pedersen NW, Hadrup SR et al (2018) T-cell responses in the microenvironment of primary renal cell carcinoma-implications for adoptive cell therapy. Cancer Immunol Res 6(2):222–235CrossRefGoogle Scholar
  34. 34.
    Tian JQ, Wang ZP, Rodriguez R, Fu JS, Lu JZ, Ma BL (2006) In vitro enhanced cytotoxicity of tumor-infiltrating lymphocytes transfected with tumor necrosis factor-related apoptosis-inducing ligand and/or interleukin-2 gene in human renal cell carcinoma. Urology 67(5):1093–1098. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    de Bruyn M, Wei Y, Wiersma VR, Samplonius DF, Klip HG, van der Zee AG, Yang B, Helfrich W, Bremer E (2011) Cell surface delivery of TRAIL strongly augments the tumoricidal activity of T cells. Clin Cancer Res 17(17):5626–5637. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Strater J, Hinz U, Hasel C, Bhanot U, Mechtersheimer G, Lehnert T, Moller P (2005) Impaired CD95 expression predisposes for recurrence in curatively resected colon carcinoma: clinical evidence for immunoselection and CD95L mediated control of minimal residual disease. Gut 54(5):661–665. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cacan E (2017) Enhancing sensitivity of chemoresistant ovarian cancer cells to TRAIL and FAS mediated apoptosis by radiation. Turk Hij Den Biyol Derg 74(3):185–192CrossRefGoogle Scholar
  38. 38.
    de Miguel D, Lemke J, Anel A, Walczak H, Martinez-Lostao L (2016) Onto better TRAILs for cancer treatment. Cell Death Differ 23(5):733–747CrossRefGoogle Scholar
  39. 39.
    Hinrichs C, Borman Z, Cassard L, Gattinoni L, Spolski R, Yu Z, Sanchez-Perez L, Muranski P, Kern S, Logun C et al (2009) Adoptively transferred effector cells derived from naïve rather than central memory CD8 T cells mediate superior antitumor immunity. PNAS 106:17469–17474CrossRefGoogle Scholar
  40. 40.
    Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, Forman SJ (2010) Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 16:1245–1256CrossRefGoogle Scholar
  41. 41.
    Poschke I, Lovgren T, Adamson L, Nystrom M, Andersson E, Hansson J et al (2014) A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma. Cancer Immunol Immunother 63(10):1061–1071CrossRefGoogle Scholar
  42. 42.
    Cesana GC, DeRaffele G, Cohen S et al (2006) Characterization of CD4*CD25* regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol 24:1169–1177CrossRefGoogle Scholar
  43. 43.
    Siddiqui SA, Frigola X, Bonne-Annee S et al (2007) Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res 13:2075–2081CrossRefGoogle Scholar
  44. 44.
    Finke JH, Rini B, Ireland J et al (2008) Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 14(20):6674–6682 Epub 2008/10/18 CrossRefGoogle Scholar
  45. 45.
    Nagaraj S, Youn JI, Weber H et al (2010) Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 16(6):1812–1823CrossRefGoogle Scholar
  46. 46.
    Nicholson IC, Mavrangelos C, Bird DR et al (2012) PI16 is expressed by a subset of human memory Treg with enhanced migration to CCL17 and CCL20. Cell Immunol 275(1–2):12–18CrossRefGoogle Scholar
  47. 47.
    Knutson KL, Wagner W, Disis ML (2006) Adoptive T cell therapy of solid cancers. Cancer Immunol Immunother 55(1):96–103CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Immunology, 2nd Faculty of Medicine and Motol University HospitalCharles UniversityPragueCzech Republic

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