Cancers

Editorial

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3 pages, 180 KiB

Open AccessEditorial

Insights into Cancer Immunotherapies: Recent Breakthroughs, Opportunities, and Challenges

by Evan G. Pappas, Michael H. Kershaw and Clare Y. Slaney

Cancers 2023, 15(4), 1322; https://doi.org/10.3390/cancers15041322 - 19 Feb 2023

Viewed by 1535

Abstract

This Special Issue reminds us that, although incredible developments have occurred in the field of cancer immunotherapy, there is still plenty of room for improvement [...] Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

4 pages, 170 KiB

Open AccessEditorial

Challenges and Opportunities for Effective Cancer Immunotherapies

by Clare Y. Slaney and Michael H. Kershaw

Cancers 2020, 12(11), 3164; https://doi.org/10.3390/cancers12113164 - 28 Oct 2020

Cited by 7 | Viewed by 2040

Abstract

Using immunotherapy to treat cancers can be traced back to the 1890s, where a New York physician William Coley used heat-killed bacteria to treat cancer patients, which became known as “Coley’s toxin” [...] Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

Research

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14 pages, 1608 KiB

Open AccessArticle

Enhancing Adoptive Cell Transfer with Combination BRAF-MEK and CDK4/6 Inhibitors in Melanoma

by Peter Kar Han Lau, Carleen Cullinane, Susan Jackson, Rachael Walker, Lorey K. Smith, Alison Slater, Laura Kirby, Riyaben P. Patel, Bianca von Scheidt, Clare Y. Slaney, Grant A. McArthur and Karen E. Sheppard

Cancers 2021, 13(24), 6342; https://doi.org/10.3390/cancers13246342 - 17 Dec 2021

Cited by 5 | Viewed by 3190

Abstract

Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there [...] Read more.

Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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15 pages, 47434 KiB

Open AccessArticle

Ropporin-1 and 1B Are Widely Expressed in Human Melanoma and Evoke Strong Humoral Immune Responses

by Jessica Da Gama Duarte, Katherine Woods, Luke T. Quigley, Cyril Deceneux, Candani Tutuka, Tom Witkowski, Simone Ostrouska, Chris Hudson, Simon Chang-Hao Tsao, Anupama Pasam, Alexander Dobrovic, Jonathan M. Blackburn, Jonathan Cebon and Andreas Behren

Cancers 2021, 13(8), 1805; https://doi.org/10.3390/cancers13081805 - 9 Apr 2021

Cited by 2 | Viewed by 4951

Abstract

Antibodies that block immune regulatory checkpoints (programmed cell death 1, PD-1 and cytotoxic T-lymphocyte-associated antigen 4, CTLA-4) to mobilise immunity have shown unprecedented clinical efficacy against cancer, demonstrating the importance of antigen-specific tumour recognition. Despite this, many patients still fail to benefit from [...] Read more.

Antibodies that block immune regulatory checkpoints (programmed cell death 1, PD-1 and cytotoxic T-lymphocyte-associated antigen 4, CTLA-4) to mobilise immunity have shown unprecedented clinical efficacy against cancer, demonstrating the importance of antigen-specific tumour recognition. Despite this, many patients still fail to benefit from these treatments and additional approaches are being sought. These include mechanisms that boost antigen-specific immunity either by vaccination or adoptive transfer of effector cells. Other than neoantigens, epigenetically regulated and shared antigens such as NY-ESO-1 are attractive targets; however, tissue expression is often heterogeneous and weak. Therefore, peptide-specific therapies combining multiple antigens rationally selected to give additive anti-cancer benefits are necessary to achieve optimal outcomes. Here, we show that Ropporin-1 (ROPN1) and 1B (ROPN1B), cancer restricted antigens, are highly expressed and immunogenic, inducing humoral immunity in patients with advanced metastatic melanoma. By multispectral immunohistochemistry, 88.5% of melanoma patients tested (n = 54/61) showed ROPN1B expression in at least 1 of 2/3 tumour cores in tissue microarrays. Antibody responses against ROPN1A and ROPN1B were detected in 71.2% of melanoma patients tested (n = 74/104), with increased reactivity seen with more advanced disease stages. Thus, ROPN1A and ROPN1B may indeed be viable targets for cancer immunotherapy, alone or in combination with other cancer antigens, and could be combined with additional therapies such as immune checkpoint blockade. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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23 pages, 4101 KiB

Open AccessArticle

Myxoma Virus Expressing LIGHT (TNFSF14) Pre-Loaded into Adipose-Derived Mesenchymal Stem Cells Is Effective Treatment for Murine Pancreatic Adenocarcinoma

by Joanna Jazowiecka-Rakus, Agata Hadrys, Masmudur M. Rahman, Grant McFadden, Wojciech Fidyk, Ewa Chmielik, Marlena Pazdzior, Maciej Grajek, Violetta Kozik and Aleksander Sochanik

Cancers 2021, 13(6), 1394; https://doi.org/10.3390/cancers13061394 - 19 Mar 2021

Cited by 16 | Viewed by 3553

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a weakly immunogenic fatal neoplasm. Oncolytic viruses with dual anti-cancer properties—oncolytic and immune response-boosting effects—have great potential for PDAC management. Adipose-derived stem cells (ADSCs) of mesenchymal origin were infected ex vivo with recombinant myxoma virus (MYXV), which encodes [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a weakly immunogenic fatal neoplasm. Oncolytic viruses with dual anti-cancer properties—oncolytic and immune response-boosting effects—have great potential for PDAC management. Adipose-derived stem cells (ADSCs) of mesenchymal origin were infected ex vivo with recombinant myxoma virus (MYXV), which encodes murine LIGHT, also called tumor necrosis factor ligand superfamily member 14 (TNFSF14). The viability and proliferation of ADSCs were not remarkably decreased (1–2 days) following MYXV infection, in sharp contrast to cells of pancreatic carcinoma lines studied, which were rapidly killed by the infection. Comparison of the intraperitoneal (IP) vs. the intravenous (IV) route of ADSC/MYXV administration revealed more pancreas-targeted distribution of the virus when ADSCs were delivered IP to mice bearing orthotopically injected PDAC. The biodistribution, tumor burden reduction and anti-tumor adaptive immune response were examined. Bioluminescence data, used to assess the presence of the luciferase-tagged virus after IP injection, indicated enhanced trafficking into the pancreata of mice bearing orthotopically-induced PDAC, as compared to tumor-free animals, resulting in extended survival of the treated PDAC-seeded animals and in the boosted expression of key adaptive immune response markers. We conclude that ADSCs pre-loaded with transgene-armed MYXV and administered IP allow for the effective ferrying of the oncolytic virus to sites of PDAC and mediate improved tumor regression. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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13 pages, 1445 KiB

Open AccessArticle

Targeting CAR to the Peptide-MHC Complex Reveals Distinct Signaling Compared to That of TCR in a Jurkat T Cell Model

by Ling Wu, Joanna Brzostek, Shvetha Sankaran, Qianru Wei, Jiawei Yap, Triscilla Y.Y. Tan, Junyun Lai, Paul A. MacAry and Nicholas R. J. Gascoigne

Cancers 2021, 13(4), 867; https://doi.org/10.3390/cancers13040867 - 18 Feb 2021

Cited by 11 | Viewed by 4522

Abstract

Chimeric antigen receptor T cells (CAR-T) utilize T cell receptor (TCR) signaling cascades and the recognition functions of antibodies. This allows T cells, normally restricted by the major histocompatibility complex (MHC), to be redirected to target cells by their surface antigens, such as [...] Read more.

Chimeric antigen receptor T cells (CAR-T) utilize T cell receptor (TCR) signaling cascades and the recognition functions of antibodies. This allows T cells, normally restricted by the major histocompatibility complex (MHC), to be redirected to target cells by their surface antigens, such as tumor associated antigens (TAAs). CAR-T technology has achieved significant successes in treatment of certain cancers, primarily liquid cancers. Nonetheless, many challenges hinder development of this therapy, such as cytokine release syndrome (CRS) and the efficacy of CAR-T treatments for solid tumors. These challenges show our inadequate understanding of this technology, particularly regarding CAR signaling, which has been less studied. To dissect CAR signaling, we designed a CAR that targets an epitope from latent membrane protein 2 A (LMP2 A) of the Epstein–Barr virus (EBV) presented on HLA*A02:01. Because of this, CAR and TCR signaling can be compared directly, allowing us to study the involvement of other signaling molecules, such as coreceptors. This comparison revealed that CAR was sufficient to bind monomeric antigens due to its high affinity but required oligomeric antigens for its activation. CAR sustained the transduced signal significantly longer, but at a lower magnitude, than did TCR. CD8 coreceptor was recruited to the CAR synapse but played a negligible role in signaling, unlike for TCR signaling. The distinct CAR signaling processes could provide explanations for clinical behavior of CAR-T therapy and suggest ways to improve the technology. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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15 pages, 1128 KiB

Open AccessArticle

Real-World Experience of Pembrolizumab Monotherapy in Patients with Recurrent or Persistent Cervical Cancer: A Korean Multi-Center Retrospective Study (KGOG1041)

by Min Chul Choi, Yong-Man Kim, Jeong-Won Lee, Yong Jae Lee, Dong Hoon Suh, Sung Jong Lee, Taek Sang Lee, Maria Lee, Dong Choon Park, Min Kyu Kim, Jong-Min Lee, Seung-Hyuk Shim, Seob Jeon, Kyung Jin Min, Mi Kyung Kim, Bo Wook Kim, Jeong Yeol Park, Byoung-Gie Kim, Dae Yeon Kim, Moon-Hong Kim, Hyun-Soo Kim and Jung-Yun Lee Show full author list Hide full author list

Cancers 2020, 12(11), 3188; https://doi.org/10.3390/cancers12113188 - 29 Oct 2020

Cited by 9 | Viewed by 3660

Abstract

This study investigated the antitumor activity and safety of pembrolizumab in patients with recurrent cervical cancer in real-world practice. We conducted a multi-center retrospective study of patients with recurrent or persistent cervical cancer treated with pembrolizumab at sixteen institutions in Korea between January [...] Read more.

This study investigated the antitumor activity and safety of pembrolizumab in patients with recurrent cervical cancer in real-world practice. We conducted a multi-center retrospective study of patients with recurrent or persistent cervical cancer treated with pembrolizumab at sixteen institutions in Korea between January 2016 and March 2020. The primary endpoints were the objective response rate (ORR) and safety. Data were available for 117 patients. The median age was 53 years (range, 28–79). Sixty-four (54.7%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. Forty-nine (41.9%) patients were stage ≥III at diagnosis. Eighty-eight (75.2%) patients had squamous cell carcinoma. The median number of prior chemotherapy lines was two (range, 1–6). During the median follow-up of 4.9 months (range, 0.2–35.3), the ORR was 9.4%, with three complete responses and eight partial responses. The median time to response was 2.8 months (range 1.3–13.1), and the median duration of response (DOR) was not reached. In the population of patients with favorable performance status (ECOG ≤1) (n = 53), the ORR was 18.9%, and the median DOR was 8.9 months (range, 7.3–10.4). Adverse events occurred in 55 (47.0%) patients, including eight (6.8%) patients who experienced grade ≥3 events, and two of them were suspicious treatment-related deaths. Pembrolizumab had modest antitumor activity in patients with recurrent cervical cancer comparable to that found in previously reported clinical trials. However, in patients with favorable performance status, pembrolizumab showed effective antitumor activity. Some safety profiles should be carefully monitored during treatment. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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10 pages, 1857 KiB

Open AccessArticle

The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC

by Viviane Ponath, Miriam Frech, Mathis Bittermann, Reem Al Khayer, Andreas Neubauer, Cornelia Brendel and Elke Pogge von Strandmann

Cancers 2020, 12(10), 2857; https://doi.org/10.3390/cancers12102857 - 3 Oct 2020

Cited by 11 | Viewed by 2955

Abstract

Drugs targeting epigenetic mechanisms such as histone deacetylase inhibitors (HDACi) suppress tumor growth. HDACi also induce the expression of ligands for the cytotoxicity receptor NKG2D rendering tumors more susceptible to natural killer (NK) cell-dependent killing. The major acetylases responsible for the expression of [...] Read more.

Drugs targeting epigenetic mechanisms such as histone deacetylase inhibitors (HDACi) suppress tumor growth. HDACi also induce the expression of ligands for the cytotoxicity receptor NKG2D rendering tumors more susceptible to natural killer (NK) cell-dependent killing. The major acetylases responsible for the expression of NKG2D ligands (NKG2D-L) are CBP and p300. The role of the oncogene and transcriptional repressor SKI, an essential part of an HDAC-recruiting co-repressor complex, which competes with CBP/p300 for binding to SMAD3 in TGFβ signaling, is unknown. Here we show that the siRNA-mediated downregulation of SKI in the pancreatic cancer cell lines Panc-1 and Patu8988t leads to an increased target cell killing by primary NK cells. However, the higher cytotoxicity of NK cells did not correlate with the induction of NKG2D-L. Of note, the expression of NKG2D-L and consequently NK cell-dependent killing could be induced upon LBH589 (LBH, panobinostat) or valproic acid (VPA) treatment irrespective of the SKI expression level but was significantly higher in pancreatic cancer cells upon genetic ablation of SKI. These data suggest that SKI represses the inducible expression of NKG2D-L. The combination of HDACi with NK cell-based immunotherapy is an attractive treatment option for pancreatic tumors, specifically for patients with high SKI protein levels. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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13 pages, 2059 KiB

Open AccessArticle

Interleukin-15 after Near-Infrared Photoimmunotherapy (NIR-PIT) Enhances T Cell Response against Syngeneic Mouse Tumors

by Yasuhiro Maruoka, Aki Furusawa, Ryuhei Okada, Fuyuki Inagaki, Hiroaki Wakiyama, Takuya Kato, Tadanobu Nagaya, Peter L. Choyke and Hisataka Kobayashi

Cancers 2020, 12(9), 2575; https://doi.org/10.3390/cancers12092575 - 10 Sep 2020

Cited by 26 | Viewed by 3323

Abstract

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is activated by 690 nm light. Cancer cell-targeted NIR-PIT induces rapid necrotic/immunogenic cell death (ICD) that induces [...] Read more.

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is activated by 690 nm light. Cancer cell-targeted NIR-PIT induces rapid necrotic/immunogenic cell death (ICD) that induces antitumor host immunity including re-priming and proliferation of T cells. Interleukin-15 (IL-15) is a cytokine that activates natural killer (NK)-, B- and T-cells while having minimal effect on regulatory T cells (Tregs) that lack the IL-15 receptor. Here, we hypothesized that IL-15 administration with cancer cell-targeted NIR-PIT could further inhibit tumor growth by increasing antitumor host immunity. Three syngeneic mouse tumor models, MC38-luc, LL/2, and MOC1, underwent combined CD44-targeted NIR-PIT and short-term IL-15 administration with appropriate controls. Comparing with the single-agent therapy, the combination therapy of IL-15 after NIR-PIT inhibited tumor growth, prolonged survival, and increased tumor infiltrating CD8+ T cells more efficiently in tumor-bearing mice. IL-15 appears to enhance the therapeutic effect of cancer-targeted NIR-PIT. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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Review

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27 pages, 1352 KiB

Open AccessReview

Nonreplicating Adenoviral Vectors: Improving Tropism and Delivery of Cancer Gene Therapy

by Nayara Gusmão Tessarollo, Ana Carolina M. Domingues, Fernanda Antunes, Jean Carlos dos Santos da Luz, Otavio Augusto Rodrigues, Otto Luiz Dutra Cerqueira and Bryan E. Strauss

Cancers 2021, 13(8), 1863; https://doi.org/10.3390/cancers13081863 - 14 Apr 2021

Cited by 8 | Viewed by 5086

Abstract

Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, [...] Read more.

Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a reduction of antiviral host responses would favor the use of adenoviral vectors in cancer immunotherapy. In this review, we describe the structural and molecular features of nonreplicating adenoviral vectors, the current limitations to their use, and strategies to modify adenoviral tropism, highlighting the approaches that may allow for the systemic administration of gene therapy. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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15 pages, 496 KiB

Open AccessReview

The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy

by Francisco J. Cueto and David Sancho

Cancers 2021, 13(7), 1525; https://doi.org/10.3390/cancers13071525 - 26 Mar 2021

Cited by 69 | Viewed by 7458

Abstract

Dendritic cells (DCs) prime anti-tumor T cell responses in tumor-draining lymph nodes and can restimulate T effector responses in the tumor site. Thus, in addition to unleashing T cell effector activity, current immunotherapies should be directed to boost DC function. Herein, we review [...] Read more.

Dendritic cells (DCs) prime anti-tumor T cell responses in tumor-draining lymph nodes and can restimulate T effector responses in the tumor site. Thus, in addition to unleashing T cell effector activity, current immunotherapies should be directed to boost DC function. Herein, we review the potential function of Flt3L as a tool for cancer immunotherapy. Flt3L is a growth factor that acts in Flt3-expressing multipotent progenitors and common lymphoid progenitors. Despite the broad expression of Flt3 in the hematopoietic progenitors, the main effect of the Flt3/Flt3L axis, revealed by the characterization of mice deficient in these genes, is the generation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). However, Flt3 signaling through PI3K and mTOR may also affect the function of mature DCs. We recapitulate the use of Flt3L in preclinical studies either as a single agent or in combination with other cancer therapies. We also analyze the use of Flt3L in clinical trials. The strong correlation between type 1 cDC (cDC1) infiltration of human cancers with overall survival in many cancer types suggests the potential use of Flt3L to boost expansion of this DC subset. However, this may need the combination of Flt3L with other immunomodulatory agents to boost cancer immunotherapy. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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23 pages, 2770 KiB

Open AccessReview

Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells

by Ali Hosseini Rad S. M., Joshua Colin Halpin, Mojtaba Mollaei, Samuel W. J. Smith Bell, Nattiya Hirankarn and Alexander D. McLellan

Cancers 2021, 13(6), 1229; https://doi.org/10.3390/cancers13061229 - 11 Mar 2021

Cited by 15 | Viewed by 5391

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the [...] Read more.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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15 pages, 1430 KiB

Open AccessReview

TAM Receptor Inhibition–Implications for Cancer and the Immune System

by Pia Aehnlich, Richard Morgan Powell, Marlies J. W. Peeters, Anne Rahbech and Per thor Straten

Cancers 2021, 13(6), 1195; https://doi.org/10.3390/cancers13061195 - 10 Mar 2021

Cited by 50 | Viewed by 5782

Abstract

Tyro3, Axl and MerTK (TAM) receptors are receptor tyrosine kinases which play important roles in efferocytosis and in the balancing of immune responses and inflammation. TAM receptor activation is induced upon binding of the ligands protein S (Pros1) or growth arrest-specific protein 6 [...] Read more.

Tyro3, Axl and MerTK (TAM) receptors are receptor tyrosine kinases which play important roles in efferocytosis and in the balancing of immune responses and inflammation. TAM receptor activation is induced upon binding of the ligands protein S (Pros1) or growth arrest-specific protein 6 (Gas6) which act as bridging molecules for binding of phosphatidyl serine (PtdSer) exposed on apoptotic cell membranes. Upon clearance of apoptotic cell material, TAM receptor activation on innate cells suppresses proinflammatory functions, thereby ensuring the immunologically silent removal of apoptotic material in the absence of deleterious immune responses. However, in T cells, MerTK signaling is costimulatory and promotes activation and functional output of the cell. MerTK and Axl are also aberrantly expressed in a range of both hematological and solid tumor malignancies, including breast, lung, melanoma and acute myeloid leukemia, where they have a role in oncogenic signaling. Consequently, TAM receptors are being investigated as therapeutic targets using small molecule inhibitors and have already demonstrated efficacy in mouse tumor models. Thus, inhibition of TAM signaling in cancer cells could have therapeutic value but given the opposing roles of TAM signaling in innate cells and T cells, TAM inhibition could also jeopardize anticancer immune responses. This conflict is discussed in this review, describing the effects of TAM inhibition on cancer cells as well as immune cells, while also examining the intricate interplay of cancer and immune cells in the tumor microenvironment. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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27 pages, 1430 KiB

Open AccessReview

Natural Killer Cells and Anti-Cancer Therapies: Reciprocal Effects on Immune Function and Therapeutic Response

by Elisa C. Toffoli, Abdolkarim Sheikhi, Yannick D. Höppner, Pita de Kok, Mahsa Yazdanpanah-Samani, Jan Spanholtz, Henk M. W. Verheul, Hans J. van der Vliet and Tanja D. de Gruijl

Cancers 2021, 13(4), 711; https://doi.org/10.3390/cancers13040711 - 9 Feb 2021

Cited by 21 | Viewed by 5561

Abstract

Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, [...] Read more.

Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, making them relevant players in antibody-based cancer therapies. The role of NK cells in other approved and experimental anti-cancer therapies is more elusive. Here, we review the possible role of NK cells in the efficacy of various anti-tumor therapies, including radiotherapy, chemotherapy, and immunotherapy, as well as the impact of these therapies on NK cell function. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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33 pages, 1094 KiB

Open AccessEditor’s ChoiceReview

Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy

by María Florencia Mercogliano, Sofía Bruni, Florencia Mauro, Patricia Virginia Elizalde and Roxana Schillaci

Cancers 2021, 13(3), 564; https://doi.org/10.3390/cancers13030564 - 2 Feb 2021

Cited by 58 | Viewed by 7200

Abstract

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) [...] Read more.

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) cells, and B and T lymphocytes. Within the tumor microenvironment, however, TNFα is one of the main mediators of cancer-related inflammation. It is involved in the recruitment and differentiation of immune suppressor cells, leading to evasion of tumor immune surveillance. These characteristics turn TNFα into an attractive target to overcome therapy resistance and tackle cancer. This review focuses on the diverse molecular mechanisms that place TNFα as a source of resistance to immunotherapy such as monoclonal antibodies against cancer cells or immune checkpoints and adoptive cell therapy. We also expose the benefits of TNFα blocking strategies in combination with immunotherapy to improve the antitumor effect and prevent or treat adverse immune-related effects. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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17 pages, 817 KiB

Open AccessReview

Chimeric Antigen Receptor beyond CAR-T Cells

by Vicky Mengfei Qin, Criselle D’Souza, Paul J. Neeson and Joe Jiang Zhu

Cancers 2021, 13(3), 404; https://doi.org/10.3390/cancers13030404 - 22 Jan 2021

Cited by 38 | Viewed by 7271

Abstract

Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate [...] Read more.

Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate a cytotoxic response against the tumour. CAR-T cell therapy has achieved remarkable success in treating hematologic malignancies, but not in solid tumours. Currently, extensive research is being carried out to make CAR-T cells a therapy for solid tumours. To date, most of the research interest in the field has focused on cytotoxic T lymphocytes as the carrier of CAR products. However, in addition to T cells, the CAR design can be introduced in other immune cells, such as natural killer (NK)/NKT cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, etc. Some of the CAR-engineered immune cells, such as CAR- γδ T and CAR-NK/NK-T cells, are directly involved in the anti-tumour response, demonstrated in preclinical studies and/or clinical trials. CAR-Tregs showed promising therapeutic potential in treating autoimmune diseases. In particular, B cells engineered with chimeric receptors can be used as a platform for long-term delivery of therapeutic proteins, such as recombinant antibodies or protein replacement, in an antigen-specific manner. CAR technology is one of the most powerful engineering platforms in immunotherapy, especially for the treatment of cancers. In this review, we will discuss the recent application of the CAR design in non-CAR-T cells and future opportunities in immunotherapy. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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25 pages, 2399 KiB

Open AccessReview

Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors

by Jim Middelburg, Kristel Kemper, Patrick Engelberts, Aran F. Labrijn, Janine Schuurman and Thorbald van Hall

Cancers 2021, 13(2), 287; https://doi.org/10.3390/cancers13020287 - 14 Jan 2021

Cited by 76 | Viewed by 14273

Abstract

Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and [...] Read more.

Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and impaired T-cell quality due to the presence of an immunosuppressive tumor microenvironment, which affect the safety and limit efficacy of CD3-bispecific antibody therapy. In this review, we provide a brief status update of the CD3-bispecific antibody therapy field and identify intrinsic hurdles in solid cancers. Furthermore, we describe potential combinatorial approaches to overcome these challenges in order to generate selective and more effective responses. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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23 pages, 1651 KiB

Open AccessReview

IL-12 Family Cytokines in Cancer and Immunotherapy

by Bhalchandra Mirlekar and Yuliya Pylayeva-Gupta

Cancers 2021, 13(2), 167; https://doi.org/10.3390/cancers13020167 - 6 Jan 2021

Cited by 159 | Viewed by 15362

Abstract

The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles [...] Read more.

The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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17 pages, 14504 KiB

Open AccessReview

Immunocyte Membrane-Coated Nanoparticles for Cancer Immunotherapy

by Ping Gong, Yifan Wang, Pengfei Zhang, Zhaogang Yang, Weiye Deng, Zhihong Sun, Mingming Yang, Xuefeng Li, Gongcheng Ma, Guanjun Deng, Shiyan Dong, Lintao Cai and Wen Jiang

Cancers 2021, 13(1), 77; https://doi.org/10.3390/cancers13010077 - 30 Dec 2020

Cited by 49 | Viewed by 6493

Abstract

Despite the advances in surface bioconjugation of synthetic nanoparticles for targeted drug delivery, simple biological functionalization is still insufficient to replicate complex intercellular interactions naturally. Therefore, these foreign nanoparticles are inevitably exposed to the immune system, which results in phagocytosis by the reticuloendothelial [...] Read more.

Despite the advances in surface bioconjugation of synthetic nanoparticles for targeted drug delivery, simple biological functionalization is still insufficient to replicate complex intercellular interactions naturally. Therefore, these foreign nanoparticles are inevitably exposed to the immune system, which results in phagocytosis by the reticuloendothelial system and thus, loss of their biological significance. Immunocyte membranes play a key role in intercellular interactions, and can protect foreign nanomaterials as a natural barrier. Therefore, biomimetic nanotechnology based on cell membranes has developed rapidly in recent years. This paper summarizes the development of immunocyte membrane-coated nanoparticles in the immunotherapy of tumors. We will introduce several immunocyte membrane-coated nanocarriers and review the challenges to their large-scale preparation and application. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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28 pages, 2811 KiB

Open AccessReview

Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged

by Stefaan W. Van Gool, Jennifer Makalowski, Simon Fiore, Tobias Sprenger, Lothar Prix, Volker Schirrmacher and Wilfried Stuecker

Cancers 2021, 13(1), 32; https://doi.org/10.3390/cancers13010032 - 24 Dec 2020

Cited by 28 | Viewed by 6238

Abstract

Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin [...] Read more.

Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor–host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor–host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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24 pages, 775 KiB

Open AccessReview

Immunocompetent Mouse Models in the Search for Effective Immunotherapy in Glioblastoma

by Roxanne Wouters, Sien Bevers, Matteo Riva, Frederik De Smet and An Coosemans

Cancers 2021, 13(1), 19; https://doi.org/10.3390/cancers13010019 - 23 Dec 2020

Cited by 15 | Viewed by 5231

Abstract

Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor [...] Read more.

Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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27 pages, 1255 KiB

Open AccessReview

Convergent Evolution by Cancer and Viruses in Evading the NKG2D Immune Response

by Richard Baugh, Hena Khalique and Leonard W. Seymour

Cancers 2020, 12(12), 3827; https://doi.org/10.3390/cancers12123827 - 18 Dec 2020

Cited by 14 | Viewed by 3890

Abstract

The natural killer group 2 member D (NKG2D) receptor and its family of NKG2D ligands (NKG2DLs) are key components in the innate immune system, triggering NK, γδ and CD8⁺ T cell-mediated immune responses. While surface NKG2DL are rarely found on healthy cells, [...] Read more.

The natural killer group 2 member D (NKG2D) receptor and its family of NKG2D ligands (NKG2DLs) are key components in the innate immune system, triggering NK, γδ and CD8⁺ T cell-mediated immune responses. While surface NKG2DL are rarely found on healthy cells, expression is significantly increased in response to various types of cellular stress, viral infection, and tumour cell transformation. In order to evade immune-mediated cytotoxicity, both pathogenic viruses and cancer cells have evolved various mechanisms of subverting immune defences and preventing NKG2DL expression. Comparisons of the mechanisms employed following virus infection or malignant transformation reveal a pattern of converging evolution at many of the key regulatory steps involved in NKG2DL expression and subsequent immune responses. Exploring ways to target these shared steps in virus- and cancer-mediated immune evasion may provide new mechanistic insights and therapeutic opportunities, for example, using oncolytic virotherapy to re-engage the innate immune system towards cancer cells. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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22 pages, 663 KiB

Open AccessReview

Modulating the Tumour Microenvironment by Intratumoural Injection of Pattern Recognition Receptor Agonists

by Olivia K. Burn, Kef K. Prasit and Ian F. Hermans

Cancers 2020, 12(12), 3824; https://doi.org/10.3390/cancers12123824 - 18 Dec 2020

Cited by 13 | Viewed by 4234

Abstract

Signalling through pattern recognition receptors (PRRs) leads to strong proinflammatory responses, enhancing the activity of antigen presenting cells and shaping adaptive immune responses against tumour associated antigens. Unfortunately, toxicities associated with systemic administration of these agonists have limited their clinical use to date. [...] Read more.

Signalling through pattern recognition receptors (PRRs) leads to strong proinflammatory responses, enhancing the activity of antigen presenting cells and shaping adaptive immune responses against tumour associated antigens. Unfortunately, toxicities associated with systemic administration of these agonists have limited their clinical use to date. Direct injection of PRR agonists into the tumour can enhance immune responses by directly modulating the cells present in the tumour microenvironment. This can improve local antitumour activity, but importantly, also facilitates systemic responses that limit tumour growth at distant sites. As such, this form of therapy could be used clinically where metastatic tumour lesions are accessible, or as neoadjuvant therapy. In this review, we summarise current preclinical data on intratumoural administration of PRR agonists, including new strategies to optimise delivery and impact, and combination studies with current and promising new cancer therapies. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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13 pages, 1077 KiB

Open AccessReview

The Origin and Immune Recognition of Tumor-Specific Antigens

by Anca Apavaloaei, Marie-Pierre Hardy, Pierre Thibault and Claude Perreault

Cancers 2020, 12(9), 2607; https://doi.org/10.3390/cancers12092607 - 12 Sep 2020

Cited by 39 | Viewed by 5848

Abstract

The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and [...] Read more.

The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and reverse immunology studies cannot provide this type of conclusive evidence. Most TSAs are coded by unmutated non-canonical transcripts that arise from cancer-specific epigenetic and splicing aberrations. When searching for TSAs, it is therefore important to perform mass spectrometry analyses that interrogate not only the canonical reading frame of annotated exome but all reading frames of the entire translatome. The majority of aberrantly expressed TSAs (aeTSAs) derive from unstable short-lived proteins that are good substrates for direct major histocompatibility complex (MHC) I presentation but poor substrates for cross-presentation. This is an important caveat, because cancer cells are poor antigen-presenting cells, and the immune system, therefore, depends on cross-presentation by dendritic cells (DCs) to detect the presence of TSAs. We, therefore, postulate that, in the untreated host, most aeTSAs are undetected by the immune system. We present evidence suggesting that vaccines inducing direct aeTSA presentation by DCs may represent an attractive strategy for cancer treatment. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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9 pages, 558 KiB

Open AccessCommentary

Immune Checkpoint Blockade in HER2-Positive Breast Cancer: What Role in Early Disease Setting?

by Cinzia Solinas, Debora Fumagalli and Maria Vittoria Dieci

Cancers 2021, 13(7), 1655; https://doi.org/10.3390/cancers13071655 - 1 Apr 2021

Cited by 6 | Viewed by 3003

Abstract

The present commentary synthesizes the current evidence on the role of the immune response in HER2-positive breast cancer. It points out the strengths and weaknesses of the findings observed so far, particularly in the early setting, including the clinical significance of scoring tumor-infiltrating [...] Read more.

The present commentary synthesizes the current evidence on the role of the immune response in HER2-positive breast cancer. It points out the strengths and weaknesses of the findings observed so far, particularly in the early setting, including the clinical significance of scoring tumor-infiltrating lymphocytes. A figure proposing research hypotheses for the implementation of immune checkpoint blockade use for patient candidates to neoadjuvant treatment is presented. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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16 pages, 1108 KiB

Open AccessPerspective

The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities

by Ashleigh S. Davey, Matthew E. Call and Melissa J. Call

Cancers 2021, 13(1), 38; https://doi.org/10.3390/cancers13010038 - 25 Dec 2020

Cited by 18 | Viewed by 3995

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B cell malignancies, improving patient survival and long-term remission. Nonetheless, over 50% of patients experience severe treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity. Differences in severity of toxic side-effects among [...] Read more.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B cell malignancies, improving patient survival and long-term remission. Nonetheless, over 50% of patients experience severe treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity. Differences in severity of toxic side-effects among anti-CD19 CARs suggest that the choice of costimulatory domain makes a significant contribution to toxicity, but comparisons are complicated by additional differences in the hinge and transmembrane (TM) domains of the most commonly used CARs in the clinic, segments that have long been considered to perform purely structural roles. In this perspective, we examine clinical and preclinical data for anti-CD19 CARs with identical antigen-binding (FMC63) and signalling (CD3ζ) domains to unravel the contributions of different hinge-TM and costimulatory domains. Analysis of clinical trials highlights an association of the CD28 hinge-TM with higher incidence of CRS and neurotoxicity than the corresponding sequences from CD8, regardless of whether the CD28 or the 4-1BB costimulatory domain is used. The few preclinical studies that have systematically varied these domains similarly support a strong and independent role for the CD28 hinge-TM sequence in high cytokine production. These observations highlight the value that a comprehensive and systematic interrogation of each of these structural domains could provide toward developing fundamental principles for rational design of safer CAR-T cell therapies. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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