Enhanced safety and efficacy of protease-regulated CAR-T cell receptors

Labanieh, Louai; Majzner, Robbie G.; Klysz, Dorota D.; Sotillo, Elena; Fisher, Chris J; Vilches-Moure, José G.; Pacheco, Kaithlen Zen B; Malipatlolla, Meena; Xu, Peng; Hui, Jessica H; Murty, Surya; Theruvath, Johanna; Mehta, Nishant A.; Yamada-Hunter, Sean A; Weber, Evan W.; Heitzeneder, Sabine; Parker, Kevin R.; Satpathy, Ansuman T.; Chang, Howard Y.; Lin, Michael Z.; Cochran, Jennifer R.; Mackall, Crystal L.

doi:10.1016/j.cell.2022.03.041

Cited by 105 publications

(102 citation statements)

References 121 publications

(125 reference statements)

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“…However, as shown here, at least in some cases it may be relatively simple to overcome this issue by rendering the CAR T cells resistant to some of the downstream effects of tonic signalling by overexpressing CJUN. An alternative strategy to address the problem of tonic signaling and to improve CAR T cell function in general is an elegant novel approach using protease-sensitive CAR constructs 35 . In this system, small molecule-mediated protease inhibition allows tight control over CAR surface expression levels, preventing early exhaustion resulting from tonic signaling, maintenance of a stem-like phenotype, and dramatically increased anti-tumor activity even when using aggregation-prone CAR constructs.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

Mause

Baker

Radhakrishnan

et al. 2021

Preprint

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T cells expressing chimeric antigen receptors have shown remarkable therapeutic activity against different types of cancer. However, their wider use has been hampered by the potential for life-threatening toxicities due to the unintended targeting of healthy cells expressing low levels of the targeted antigen. We have now developed an affinity-tuning approach for the generation of minimally modified, low-affinity antibody variants derived from existing high-affinity antibodies. Using this approach, we engineered a low affinity variant of the fully human CD229-specific antibody 2D3. Parental 2D3 efficiently targeted multiple myeloma cells but also healthy T cells expressing low levels of CD229. We demonstrate that CAR T cells based on a low affinity variant of 2D3 maintain the parental antibody's anti-tumor activity, but lack its targeting of healthy T cells. In addition, variant CD229 CAR T cells show reduced trogocytosis potentially augmenting CAR T cell persistence. The fast off-rate CAR produced using our affinity tuning approach eliminates a key liability of CD229 CAR T cells and paves the way for the effective and safe treatment of patients with multiple myeloma.

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Section: Discussionmentioning

confidence: 99%

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

Mause

Baker

Radhakrishnan

et al. 2021

Preprint

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“…Recently, SNIP CAR-T cells were engineered with a protease-based platform to control CAR-T cell activity with an FDA approved small molecule, allowing to switch-off CAR activity by dose interruption of the drug. 72 This novel design also circumvents on-target off-tumor activity and rapid T cell exhaustion, which may be observed with classical CAR-T cells.…”

Section: Modular Car-t Cells and Safety Switchesmentioning

confidence: 99%

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

et al. 2022

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T cell engaging therapies, like CAR-T cells and T cell engagers, redirect T cells toward tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing. T cell receptor or CAR-T downstream signaling triggers a release of pro-inflammatory cytokines, which can induce a Cytokine Release Syndrome (CRS). The incidence of CRS is still hardly predictable among individuals and remains one of the major dose-limiting safety liabilities associated with on-target activity of T cell engaging therapies. This emphasizes the need to elaborate mitigation strategies, which reduce cytokine release while retaining efficacy. Here, we review pre-clinical and clinical approaches applied for the management of CRS symptoms in the context of T cell engaging therapies, highlighting the use of tyrosine kinase inhibitors as an emerging mitigation strategy. In particular, we focus on the effects of Bruton’s tyrosine kinase (BTK), Src family including Lck, mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK) inhibitors on T cell functionality and cytokine release, to provide a rationale for their use as mitigation strategies against CRS in the context of T cell engaging therapies.

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“…TNBC is a complex disease, and requires the integration strategies for TNBC treatment, with more comprehensive diagnoses utilizing genomic analysis and transcriptomic analysis at one end and combinatorial treatment strategies at the other end ( Figure 6 ). In addition, the improvements of ACT for TNBC treatment are also required to overcome the current limitations in clinics, including many strategies such as the installation of a safety switch ( 155 ), target selection, immune cell function enhancement strategies ( 156 ), and the combinatorial strategies ( Figure 7 ).…”

Section: Challenges and Opportunities In Tnbc Immunotherapymentioning

confidence: 99%

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

Luo

Wang

et al. 2022

Front. Oncol.

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Breast cancer is the most commonly diagnosed cancer (estimated 2.3 million new cases in 2020) and the leading cause of cancer death (estimated 685,000 deaths in 2020) in women globally. Breast cancers have been categorized into four major molecular subtypes based on the immunohistochemistry (IHC) expression of classic hormone and growth factor receptors including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as a proliferation marker Ki-67 protein expression. Triple-negative breast cancer (TNBC), a breast cancer subtype lacking ER, PR, and HER2 expression, is associated with a high metastatic potential and poor prognosis. TNBC accounts for approximately only 15%–20% of new breast cancer diagnoses; it is responsible for most breast cancer–related deaths due to the lack of targeted treatment options for this patient population, and currently, systemic chemotherapy, radiation, and surgical excision remain the major treatment modalities for these patients with TNBC. Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden and high tumor-infiltrating lymphocytes, resembling the features observed on melanoma or lung cancers, which can benefit from the treatment of immune checkpoint inhibitors (ICIs). Therefore, the immunogenic nature of this aggressive disease has presented an opportunity for the development of TNBC-targeting immunotherapies. The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment. In addition, immunotherapy becomes an active research area, both in the cancer biology field and in the oncology field. In this review, we will extend our coverage on recent discoveries in preclinical research and early results in clinical trials from immune molecule-based therapy including cytokines, monoclonal antibodies, antibody–drug conjugates, bi-specific or tri-specific antibodies, ICIs, and neoantigen cancer vaccines; oncolytic virus-based therapies and adoptive immune cell transfer–based therapies including TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, and T-cell receptor-T. In the end, we will list a series of the challenges and opportunities in immunotherapy prospectively and reveal novel technologies such as high-throughput single-cell sequencing and CRISPR gene editing-based screening to generate new knowledges of immunotherapy.

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Enhanced safety and efficacy of protease-regulated CAR-T cell receptors

Cited by 105 publications

References 121 publications

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

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