<scp>CAR</scp><scp>T</scp>‐cells merge into the fast lane of cancer care

Frey, Noelle V.; Porter, David

doi:10.1002/ajh.24238

Cited by 37 publications

(17 citation statements)

References 37 publications

(101 reference statements)

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“…Clinical trials for haematological malignancies using patient T cells armed with activating, tumor-specific chimeric antigen receptors (CARs) have achieved unprecedented remission rates (recently reviewed in 35 ). CAR T cells targeting CD19 have brought 70 to 90% of patients with refractory or relapsed ALL into remission 36,37 .…”

Section: Safety and Efficacy Considerationsmentioning

confidence: 99%

TriKEs and BiKEs join CARs on the cancer immunotherapy highway

Tay

Carol

Biro

2016

Human Vaccines & Immunotherapeutics

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Unprecedented clinical success has recently been achieved in cancer immunotherapy using cytotoxic T cells armed with activating tumor-specific Chimeric Antigen Receptors (CARs). Natural killer (NK) cells, potent cytotoxic effectors, also hold potential to be effectively harnessed for immunotherapy. The anti-tumor efficacy of NK cell therapies has been limited by a lack of antigen specificity and the poor persistence of NK cells in vivo. To address these limitations, Vallera and colleagues developed novel Trispecific Killer cell Engagers (TriKEs), reported in the Feb. 2016 issue of Clinical Cancer Research.1 The novel TriKE immunomodulator evolved from the Bispecific Killer cell Engager (BiKE), a precursor developed by the same team. BiKEs comprise 2 antibody fragments, a first recognizing a tumor antigen and a second directed against CD16 on NK cells, which together trigger antibody-dependent cell-mediated cytotoxicity. IL-15 was further integrated to create TriKEs in order to drive NK cell expansion. Compared to BiKEs, TriKEs elicit far superior NK cytotoxicity and NK cell persistence in a xenograft tumor model in vivo, and are proposed to be effective adjuncts to existing NK transfer protocols. Importantly, TriKEs provide a versatile and cost-effective platform onto which novel targeting ligands can be incorporated and hold the potential to stimulate endogenous NK cells in order to circumvent the need for cell transfers altogether, heralding a new generation of immunotherapeutics.

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Section: Safety and Efficacy Considerationsmentioning

confidence: 99%

TriKEs and BiKEs join CARs on the cancer immunotherapy highway

Tay

Carol

Biro

2016

Human Vaccines & Immunotherapeutics

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“…Clinically, CAR T cells are increasingly demonstrating success for the treatment of cancers [289–292] and have been proposed for use in combatting HIV viral reservoirs [293, 294]. Furthermore, the first clinical use of “off-the-shelf” CAR T-cells in an infant who was administered the therapy on a compassionate basis in the UK was recently reported to demonstrate safety and efficacy [295], and makes the universal applicability and potential of HIV-specific CAR T cell therapy more viable.…”

Section: Adding Non-native Functions To Bnabsmentioning

confidence: 99%

Engineering broadly neutralizing antibodies for HIV prevention and therapy

Hua

Ackerman

2016

Advanced Drug Delivery Reviews

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A combination of advances spanning from isolation to delivery of potent HIV-specific antibodies have begun to revolutionize understandings of antibody-mediated antiviral activity. As a result, the set of broadly neutralizing and highly protective antibodies have grown in number, diversity, potency, and breadth of viral recognition and neutralization. These antibodies are now being further enhanced by rational engineering of their anti-HIV activities and coupled to cutting edge gene delivery and strategies to optimize their pharmacokinetics and biodistribution. As a result, the prospects for clinical use of HIV-specific antibodies to treat, clear, and prevent HIV infection are gaining momentum. Here we discuss the diverse methods whereby antibodies are being optimized for neutralization potency and breadth, biodistribution, pharmacokinetics, and effector function with the aim of revolutionizing HIV treatment and prevention options.

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“…Genetically modified CAR-T cells (CAR-Ts) have been remarkably successful in the treatment of various B-lymphoid malignancies, in particular of Acute Lymphoblastic Leukemia (ALL) in children and young adults with poor prognosis [13–16]. CD19 therefore clearly is a useful target for antigen-specific immunotherapy, provided an appropriate molecular format of the therapeutic agent is chosen.…”

Section: Introductionmentioning

confidence: 99%

“…BiTE and CAR-T cell approaches rely on cytotoxic T lymphocytes (CTLs) for the elimination of cancer cells [11, 13–16]. Although highly effective in many cases, these approaches still leave room for future improvements.…”

Section: Introductionmentioning

confidence: 99%

CD19-specific triplebody SPM-1 engages NK and γδ T cells for rapid and efficient lysis of malignant B-lymphoid cells

et al. 2016

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Triplebodies are antibody-derived recombinant proteins carrying 3 antigen-binding domains in a single polypeptide chain. Triplebody SPM-1 was designed for lysis of CD19-bearing malignant B-lymphoid cells through the engagement of CD16-expressing cytolytic effectors, including NK and γδ T cells.SPM-1 is an optimized version of triplebody ds(19-16-19) and includes humanization, disulfide stabilization and the removal of potentially immunogenic sequences. A three-step chromatographic procedure yielded 1.7 - 5.5 mg of purified, monomeric protein per liter of culture medium. In cytolysis assays with NK cell effectors, SPM-1 mediated potent lysis of cancer-derived B cell lines and primary cells from patients with various B-lymphoid malignancies, which surpassed the ADCC activity of the therapeutic antibody Rituximab. EC50-values ranged from 3 to 86 pM. Finally, in an impedance-based assay, SPM-1 mediated a particularly rapid lysis of CD19-bearing target cells by engaging and activating both primary and expanded human γδ T cells from healthy donors as effectors.These data establish SPM-1 as a useful tool for a kinetic analysis of the cytolytic reactions mediated by γδ T and NK cells and as an agent deserving further development towards clinical use for the treatment of B-lymphoid malignancies.

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CART‐cells merge into the fast lane of cancer care

Cited by 37 publications

References 37 publications

TriKEs and BiKEs join CARs on the cancer immunotherapy highway

TriKEs and BiKEs join CARs on the cancer immunotherapy highway

Engineering broadly neutralizing antibodies for HIV prevention and therapy

CD19-specific triplebody SPM-1 engages NK and γδ T cells for rapid and efficient lysis of malignant B-lymphoid cells

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