Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective

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Abstract

The term “cancer stem cells” (CSCs) commonly refers to a subset of tumor cells endowed with stemness features, potentially involved in chemo-resistance and disease relapses. CSCs may present peculiar immunogenic features influencing their homeostasis within the tumor microenvironment. The susceptibility of CSCs to recognition and targeting by the immune system is a relevant issue and matter of investigation, especially considering the multiple emerging immunotherapy strategies. Adoptive cellular immunotherapies, especially those strategies encompassing the genetic redirection with chimeric antigen receptors (CAR), hold relevant promise in several tumor settings and might in theory provide opportunities for selective elimination of CSC subsets. Initial dedicated preclinical studies are supporting the potential targeting of CSCs by cellular immunotherapies, indirect evidence from clinical studies may be derived and new studies are ongoing. Here we review the main issues related to the putative immunogenicity of CSCs, focusing on and highlighting the existing evidence and opportunities for cellular immunotherapy approaches with T and non-T antitumor lymphocytes.

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Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.

Robert D. Schreiber, Lloyd J. Old, Mark J. Smyth (2011)

Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

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Chimeric antigen receptor T cells for sustained remissions in leukemia.

Shannon Maude, Noelle Frey, Pamela Shaw … (2014)

Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

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Prospective identification of tumorigenic breast cancer cells.

M Al-Hajj, M S Wicha, A. Benito-Hernandez … (2003)

Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44(+)CD24(-/low)Lineage(-) in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44(+)CD24(-/low)Lineage(-) tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.

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Author and article information

Contributors

Amancio Carnero: Role: Academic Editor

Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 04 March 2021

Publication date Collection: March 2021

Volume: 10

Issue: 3

Electronic Location Identifier: 543

Affiliations

[1 ]Department of Oncology, University of Turin, 10124 Turin, Italy; chiara.donini@ 123456unito.it (C.D.); alessia.proment@ 123456edu.unito.it (A.P.); massimo.aglietta@ 123456unito.it (M.A.)

[2 ]Candiolo Cancer Institute, FPO–IRCCS, Str. Prov. 142, km 3,95, 10060 Candiolo (TO), Italy; ramona.rotolo@ 123456ircc.it (R.R.); valeria.leuci@ 123456ircc.it (V.L.)

Author notes

[* ]Correspondence: dario.sangiolo@ 123456ircc.it ; Tel.: +39-011-993-3503; Fax: +39-011-993-3522

[†]

The Authors equally contributed to the present study.

Author information

Chiara Donini https://orcid.org/0000-0003-1988-9762

Ramona Rotolo https://orcid.org/0000-0002-8544-115X

Valeria Leuci https://orcid.org/0000-0003-3592-9779

Article

Publisher ID: cells-10-00543

DOI: 10.3390/cells10030543

PMC ID: 8001974

PubMed ID: 33806296

SO-VID: 4974debe-0bc3-43b3-8e2a-cb7da311937f

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective

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Universal stem cells

Most cited references 231

Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.

Chimeric antigen receptor T cells for sustained remissions in leukemia.

Prospective identification of tumorigenic breast cancer cells.

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