Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2024

Open Access 01-12-2024 | Breast Cancer | Research

Adoptive cell transfer therapy with ex vivo primed peripheral lymphocytes in combination with anti-PDL1 therapy effectively inhibits triple-negative breast cancer growth and metastasis

Authors: Odd L. Gammelgaard, Mikkel G. Terp, Alexei F. Kirkin, Simone Johansen, Sofie Traynor, Henriette Vever, Per Guldberg, Annette R. Kodahl, Morten F. Gjerstorff, Henrik J. Ditzel

Published in: Molecular Cancer | Issue 1/2024

Login to get access

Abstract

Background

Adoptive cell transfer cancer immunotherapy holds promise for treating disseminated disease, yet generating sufficient numbers of lymphocytes with anti-cancer activity against diverse specificities remains a major challenge. We recently developed a novel procedure (ALECSAT) for selecting, expanding and maturating polyclonal lymphocytes from peripheral blood with the capacity to target malignant cells.

Methods

Immunodeficient mice were challenged with triple-negative breast cancer cell lines or patient-derived xenografts (PDX) and treated with allogeneic or autologous ALECSAT cells with and without anti-PDL1 therapy to assess the capacity of ALECSAT cells to inhibit primary tumor growth and metastasis.

Results

ALECSAT mono therapy inhibited metastasis, but did not inhibit primary tumor growth or prolong survival of tumor-bearing mice. In contrast, combined ALECSAT and anti-PDL1 therapy significantly inhibited primary tumor growth, nearly completely blocked metastasis, and prolonged survival of tumor-bearing mice.

Conclusions

Combined ALECSAT and anti-PDL1 therapy results in favorable anti-cancer responses in both cell line-derived xenograft and autologous PDX models of advanced triple-negative breast cancer.
Appendix
Available only for authorised users
Literature
1.
Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.PubMedPubMedCentralCrossRef
2.
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.PubMedPubMedCentralCrossRef
3.
Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54.PubMedPubMedCentralCrossRef
4.
JBAG Haanen MR, T.H. Borch, J.H. van den Berg, Ö. Met2, M. Geukes Foppen, J. Stoltenborg Granhøj, B. Nuijen, C. Nijenhuis, J.H. Beijnen, I. Jedema, M. van Zon, I. Mansfield Noringriis, R. Kessels, S. Wilgenhof, H.V. van Thienen, F. Lalezari, A.C.J. van Akkooi, M. Donia, I. Svane. LBA3 - Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial. 2022.
5.
6.
Del Bufalo F, De Angelis B, Caruana I, Del Baldo G, De Ioris MA, Serra A, et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N Engl J Med. 2023;388(14):1284–95.PubMedCrossRef
7.
8.
Kirkin AF, Dzhandzhugazyan KN, Guldberg P, Fang JJ, Andersen RS, Dahl C, et al. Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells. Nat Commun. 2018;9(1):785.PubMedPubMedCentralCrossRef
9.
Werlenius K, Stragliotto G, Strandeus M, Blomstrand M, Caren H, Jakola AS, et al. A randomized phase II trial of efficacy and safety of the immunotherapy ALECSAT as an adjunct to radiotherapy and temozolomide for newly diagnosed glioblastoma. Neurooncol Adv. 2021;3(1):vdab156.PubMedPubMedCentral
10.
Terp MG, Olesen KA, Arnspang EC, Lund RR, Lagerholm BC, Ditzel HJ, et al. Anti-human CD73 monoclonal antibody inhibits metastasis formation in human breast cancer by inducing clustering and internalization of CD73 expressed on the surface of cancer cells. J Immunol. 2013;191(8):4165–73.PubMedCrossRef
11.
Gjerstorff MF, Traynor S, Gammelgaard OL, Johansen S, Pedersen CB, Ditzel HJ, et al. PDX Models: a versatile tool for studying the role of myeloid-derived suppressor cells in breast cancer. Cancers (Basel). 2022;14(24):6153.PubMedCrossRef
12.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21.PubMedCrossRef
13.
Madsen JG, Schmidt SF, Larsen BD, Loft A, Nielsen R, Mandrup S. iRNA-seq: computational method for genome-wide assessment of acute transcriptional regulation from total RNA-seq data. Nucleic Acids Res. 2015;43(6):e40.PubMedPubMedCentralCrossRef
14.
15.
Hochweller K, Wabnitz GH, Samstag Y, Suffner J, Hammerling GJ, Garbi N. Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc Natl Acad Sci U S A. 2010;107(13):5931–6.PubMedPubMedCentralCrossRef
16.
Klebanoff CA, Gattinoni L, Palmer DC, Muranski P, Ji Y, Hinrichs CS, et al. Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice. Clin Cancer Res. 2011;17(16):5343–52.PubMedPubMedCentralCrossRef
17.
Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2012;18(24):6758–70.PubMedPubMedCentralCrossRef
18.
Itzhaki O, Hovav E, Ziporen Y, Levy D, Kubi A, Zikich D, et al. Establishment and large-scale expansion of minimally cultured “young” tumor infiltrating lymphocytes for adoptive transfer therapy. J Immunother. 2011;34(2):212–20.PubMedCrossRef
19.
Mousset CM, Hobo W, Woestenenk R, Preijers F, Dolstra H, van der Waart AB. Comprehensive phenotyping of T cells using flow cytometry. Cytometry A. 2019;95(6):647–54.PubMedCrossRef
20.
Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest. 2005;115(6):1616–26.PubMedPubMedCentralCrossRef
21.
Schmid P, Chui SY, Emens LA. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. Reply N Engl J Med. 2019;380(10):987–8.PubMed
22.
Miles D, Gligorov J, Andre F, Cameron D, Schneeweiss A, Barrios C, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994–1004.PubMedCrossRef
23.
Gammelgaard OL, Terp MG, Preiss B, Ditzel HJ. Human cancer evolution in the context of a human immune system in mice. Mol Oncol. 2018;12(10):1797–810.PubMedPubMedCentralCrossRef
24.
Gammelgaard OL, Terp MG, Renn C, Labrijn AF, Hamaker O, Nielsen AY, et al. Targeting two distinct epitopes on human CD73 with a bispecific antibody improves anticancer activity. J Immunother Cancer. 2022;10(9):e004554.PubMedPubMedCentralCrossRef
25.
Haslam A, Prasad V. Estimation of the Percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2(5):e192535.PubMedPubMedCentralCrossRef
26.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol. 2013;31(7):860–7.PubMedCrossRef
27.
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.PubMedCrossRef
28.
Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32(27):2959–66.PubMedPubMedCentralCrossRef
29.
Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387(3):217–26.PubMedCrossRef
30.
31.
Hinrichs CS, Borman ZA, Cassard L, Gattinoni L, Spolski R, Yu Z, et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci U S A. 2009;106(41):17469–74.PubMedPubMedCentralCrossRef
32.
Hinrichs CS, Borman ZA, Gattinoni L, Yu Z, Burns WR, Huang J, et al. Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. Blood. 2011;117(3):808–14.PubMedPubMedCentralCrossRef
33.
Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci U S A. 2005;102(27):9571–6.PubMedPubMedCentralCrossRef
34.
Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci U S A. 2004;101(7):1969–74.PubMedPubMedCentralCrossRef
35.
Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest. 2008;118(1):294–305.PubMedCrossRef
36.
Wang X, Berger C, Wong CW, Forman SJ, Riddell SR, Jensen MC. Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice. Blood. 2011;117(6):1888–98.PubMedPubMedCentralCrossRef
37.
Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunother. 2012;35(9):651–60.PubMedPubMedCentralCrossRef
38.
Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–7.PubMedPubMedCentralCrossRef
39.
Hendriks J, Xiao Y, Borst J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J Exp Med. 2003;198(9):1369–80.PubMedPubMedCentralCrossRef
40.
Buchholz VR, Flossdorf M, Hensel I, Kretschmer L, Weissbrich B, Graf P, et al. Disparate individual fates compose robust CD8+ T cell immunity. Science. 2013;340(6132):630–5.PubMedCrossRef
41.
De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994;264(5159):703–7.PubMedCrossRef
42.
Economopoulos V, Noad JC, Krishnamoorthy S, Rutt BK, Foster PJ. Comparing the MRI appearance of the lymph nodes and spleen in wild-type and immuno-deficient mouse strains. PLoS ONE. 2011;6(11):e27508.PubMedPubMedCentralCrossRef
43.
Manz MG. Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity. 2007;26(5):537–41.PubMedCrossRef
44.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7–h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37.PubMedPubMedCentralCrossRef
Metadata
Title
Adoptive cell transfer therapy with ex vivo primed peripheral lymphocytes in combination with anti-PDL1 therapy effectively inhibits triple-negative breast cancer growth and metastasis
Authors
Odd L. Gammelgaard
Mikkel G. Terp
Alexei F. Kirkin
Simone Johansen
Sofie Traynor
Henriette Vever
Per Guldberg
Annette R. Kodahl
Morten F. Gjerstorff
Henrik J. Ditzel
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2024
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-023-01914-8

Other articles of this Issue 1/2024

Molecular Cancer 1/2024 Go to the issue

Research

Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma

Research

Resistance of HNSCC cell models to pan-FGFR inhibition depends on the EMT phenotype associating with clinical outcome

Research

CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation

Review

Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application

Research

Genome-wide in vivo CRISPR screen identifies TGFβ3 as actionable biomarker of palbociclib resistance in triple negative breast cancer

Review

CTLs heterogeneity and plasticity: implications for cancer immunotherapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits