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Axicabtagene Ciloleucel, a First-In-Class CAR T Cell Therapy for Aggressive NHL

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Axicabtagene Ciloleucel, a First-In-Class CAR T Cell Therapy for Aggressive NHL Leukemia & Lymphoma ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20 Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL Zachary J. Roberts, Marc Better, Adrian Bot, Margo R. Roberts & Antoni Ribas To cite this article: Zachary J. Roberts, Marc Better, Adrian Bot, Margo R. Roberts & Antoni Ribas (2017): Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL, Leukemia & Lymphoma, DOI: 10.1080/10428194.2017.1387905 To link to this article: http://dx.doi.org/10.1080/10428194.2017.1387905 © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group View supplementary material Published online: 23 Oct 2017. Submit your article to this journal Article views: 699 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [UCLA Library] Date: 07 November 2017, At: 12:06 LEUKEMIA & LYMPHOMA, 2017 https://doi.org/10.1080/10428194.2017.1387905 REVIEW Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL Zachary J. Robertsa, Marc Bettera, Adrian Bota, Margo R. Robertsa and Antoni Ribasb aKite Pharma, Santa Monica, CA, USA; bDepartment of Medicine, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA ABSTRACT ARTICLE HISTORY The development of clinically functional chimeric antigen receptor (CAR) T cell therapy is the cul- Received 2 June 2017 mination of multiple advances over the last three decades. Axicabtagene ciloleucel (formerly Revised 18 September 2017 KTE-C19) is an anti-CD19 CAR T cell therapy in development for patients with refractory diffuse Accepted 26 September 2017 large B cell lymphoma (DLBCL), including transformed follicular lymphoma (TFL) and primary KEYWORDS mediastinal B cell lymphoma (PMBCL). Axicabtagene ciloleucel is manufactured from patients’ CAR T cells; axicabtagene own peripheral blood mononuclear cells (PBMC) during which T cells are engineered to express ciloleucel; adoptive cell a CAR that redirects them to recognize CD19-expressing cells. Clinical trials have demonstrated transfer therapy; refractory the feasibility of manufacturing axicabtagene ciloleucel in a centralized facility for use in multi- DLBCL; immunotherapy; center clinical trials and have demonstrated potent antitumor activity in patients with refractory KTE-C19 DLBCL. Main acute toxicities are cytokine release syndrome and neurologic events. Axicabtagene ciloleucel holds promise for the treatment of patients with CD19-positive malignancies, including refractory DLBCL. Introduction typically an antibody-derived single chain variable fragment (scFv) that recognizes a tumor cell surface Rationale for and description of axicabtagene protein. The scFv is linked to intracellular signaling ciloleucel components derived from T lymphocytes, including The immune system is the body’s main defense the key intracellular signaling domain of the TCR CD3f against infection and has been shown to harbor the subunit [3]. Although essential for T cell activation, sig- potential to recognize and kill cancer cells [1]. T cells naling via CD3f is not sufficient for optimal T cell func- have emerged as central players in the immune tion. Therefore, current CARs also include the response to cancer [2]. Upon engagement of tumor intracellular signaling domain of a costimulatory recep- cells by T cells expressing tumor antigen-specific T cell tor, such as CD28 or 4-1BB, which provides additional receptors (TCRs), the T cells are activated, undergo clo- signals to optimize performance (Figure 1(B))[4,5]. nal proliferation to broaden the attack, and release CARs redirect T cells to target tumor cells in a major cytokines that can enhance antitumor activity, ultim- Downloaded by [UCLA Library] at 12:06 07 November 2017 histocompatibility complex-independent fashion, ately leading to the lysis of tumor cells. However, the ideally sparing normal cells, but at a minimum limiting immune system’s ability to eradicate cancer cells is on-target/off-tumor activity to nonessential tissues, limited by several obstacles, including insufficient depending on the antigen target. CARs are typically numbers of T cells specific to tumor-specific antigens, introduced to patients’ blood-derived T cells ex vivo a series of immune checkpoints that limit full T cell via a viral vector system. CAR T cells are then activation against cancer, and the immune suppressive expanded and administered back to patients who tumor microenvironment (Figure 1(A)). Chimeric anti- have been conditioned with a lymphodepleting gen receptor (CAR) T cell therapy may overcome some chemotherapy regimen that primes the patient for of the main limitations of the endogenous immune optimal CAR T cell in vivo expansion and antitumor system and of other cancer immunotherapies, provid- activity [6–8]. ing a new avenue to treat cancer. CARs are synthetic The development of axicabtagene ciloleucel origi- immunoreceptors whose extracellular domain is nated from earlier preclinical work conducted by CONTACT Antoni Ribas [email protected] Department of Medicine, University of California Los Angeles Jonsson Comprehensive Cancer Center, 11-934 Factor Bldg., 10833 Le Conte Avenue, Los Angeles 90095, CA, USA ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by- nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 2 Z. J. ROBERTS ET AL. (A) 1 Limited number of tumor-specificecific T ccellsells Manufacture large numbers of tumor-specific T cells by CAR transduction and ex vivo expansion of autologous blood lymphocytes T cell Tumor Administer preconditioning treatment to optimize post-infusion expansion 2 Suboptimal immune cell activation and function Incorporate requisite immune-signaling domains into CAR constructs to achieve optimal T cell activity (B) Tumor Cancer cell Target antigen T cell Target binding domain Hinge Costimulatory domain • Cytolytic activity • Cytokine release • Proliferation Essential activating domain CAR-engineered T cell Figure 1. Key hurdles of antitumor immunity in B cell malignancies and how CAR technology may solve them (A), and schematic representation of a CAR (B). James Kochenderfer and Steven A. Rosenberg at the studies laid the groundwork for the first clinical report Downloaded by [UCLA Library] at 12:06 07 November 2017 Surgery Branch of the National Cancer Institute (NCI, to describe successful anti-CD19 CAR T cell therapy Bethesda, MD). The CD19-specific CAR of axicabtagene [11]. ciloleucel comprises an extracellular scFv specific for Based on the early CD19 CAR experience from the CD19 and the signaling domains of CD3f and CD28, NCI, axicabtagene ciloleucel has been generated using and was first described by Kochenderfer and col- a modified manufacturing process optimized for multi- leagues in 2009 [9]. That study demonstrated that pri- center clinical trials in aggressive non-Hodgkin lymph- mary human T cells expressing this anti-CD19 CAR oma (NHL) and other indications and for potential could produce cytokines specifically in response to future commercial applications. CD19 þ target cells and efficiently kill primary chronic lymphocytic leukemia (CLL) cells in vitro. In a later Epidemiology and treatment of aggressive B cell study, a CAR of similar design, but specific for murine lymphomas CD19 and bearing intracellular signaling domains of murine origin, was evaluated in an immune competent NHL is the seventh most common cancer in the syngeneic mouse model of lymphoma [10]. Potent United States, with an estimated 73,000 new cases in antilymphoma activity of anti-CD19 CAR T cells was 2016 [12] and several subtypes. The most prevalent observed together with the expected on-target/off- subtype of NHL is diffuse large B cell lymphoma tumor effect of normal B-cell aplasia. These preclinical (DLBCL), an aggressive disease that accounts for AXICABTAGENE CILOLEUCEL FOR LYMPHOMA 3 30–40% of NHL cases [13]. Transformed follicular 26% and a median OS of 6.3 months in patients with lymphoma (TFL) and primary mediastinal B cell lymph- refractory DLBCL [21]. This uniformly poor outcome oma (PMBCL) are rarer types of NHL [14,15]. TFL is an represents a significant unmet medical need, and aggressive form of the generally indolent follicular patients in this clinical predicament are in need of lymphoma (FL) that develops in 2–3% of FL cases per novel and efficacious treatment approaches. It is in year [16]. Although the median overall survival (OS) of patients with refractory aggressive NHL that axicabta- FL is 15 to >20 years [17,18], the median OS of TFL is gene ciloleucel is being investigated in the ZUMA-1 poor, ranging from 2.5 months to 2.5 years [14]. clinical trial. PMBCL constitutes 2–4% of NHL cases [15] and is also associated with poor outcomes [15,19]. Manufacturing axicabtagene ciloleucel First-line treatment for patients with DLBCL, PMBCL, or TFL generally consists of combination therapy with CAR T cell production processes at academic centers rituximab and chemotherapy [13,19,20]. Most new conducting single-center
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