Is cell therapy the answer for hematological malignancies?

KEYWORDS:

• Cell therapy
• hematological malignancies
• CAR-T

1. Introduction

Recent remarkable progresses achieved in the field of human cell-based therapies have led to promising opportunities and therapeutic advances in the management of some hematological malignancies (HM) [1,2]. Indeed, the introduction in clinical practice of chimeric antigen receptor T cells (CAR-T) to treat B-cell malignancies, or alternative cell-based approaches to modulate the immunologic response against HM, have allowed outstanding success of translational research [3,4], potentially opening a new era in oncology [2,5]. An interesting review recently published in this journal summarized the evolution of cell therapy, including the promising role of these new cell-based treatments, as well as some concerns related to their use in clinical practice [1]. Based on their long experience, the authors provided a clinical point of view of the current position of these cell-based therapies in the treatment algorithm, influenced by the continuous introduction of innovative treatments, such as checkpoint inhibitors, antibody-drug conjugates, and bi-specific T-cell engagers [6–8].

The history of cellular therapies for HM began with allogeneic stem cell transplantation (SCT), the most common form of adoptive cell-based immunotherapy, being its eradicating effects partially mediated by newly reconstituted immune cells (graft versus leukemia/lymphoma). In addition, the donor lymphocyte infusion using unmodified or manipulated cells represents a traditional form of cellular immunotherapy applied for several decades in patients relapsing after allogeneic SCT, or with high risk disease in remission [9]. It is only from these studies that the development of genetic engineering techniques and cellular technologies have been possible [5], reaching the most modern cell therapy models, such as CAR-T and cell receptor (transgenic TCR) redirected T cells [1]. The most accessible cellular target serving as the focus of CAR-T cell therapy was the CD19 membrane glycoprotein, which is invariably expressed by both normal and malignant lymphocytes [1]. Previous pivotal and early phase studies reported high rates of sustained remission in patients with advanced and highly pretreated B-cell acute lymphoblastic leukemia (B-ALL) and encouraging data in the setting of other B-cell neoplasm, such as B-cell non-Hodgkin’s lymphomas (NHL), chronic lymphocytic leukemia, and multiple myeloma; in the latter setting, efforts to target myeloma antigens, such as B-cell maturation antigen (CD138 and kappa-light chain), as well as CD19 on putative myeloma stem cells using CAR-T cell technology are ongoing [1,10]. Unfortunately, the same fascinating results are not obtained in the development of CAR-T cells for myeloid neoplasm, given the relative lack of specificity for targetable molecules, although the presence of some tumor-selective targets, such as CD33 and CD123 [1], may be the basis of promising approaches.

Preliminary results of CAR T-cell therapies in B-cell malignancies provided by global multicenter phase 2 trials [3,4] led to the recent approval by the U.S. Food and Drug Administration (FDA) of the first two CTL019, such as tisagenlecleucel for the treatment of relapsed or refractory (R/R) pediatric and young patients with B-cell ALL and axicabtagene ciloleucel for adults affected by R/R B-cell NHLs. The FDA approval of tisagenlecleucel was largely based on a single-arm multicenter trial, the ELIANA study, whose results are currently available only after an interim analysis and in abstract form [3]. In this study, including 88 R/R CD19 positive B-ALL patients, 52 (83%) of 63 patients evaluable for interim analysis achieved CR within 3 months of CTL019 infusion. In addition, overall survival and event-free survival at 6 months were 89% and 75%, respectively, although the treatment was not devoid of toxicities provided by CAR-T [11,12]. The latter can be a challenging concern [1,11,12] and consisted in the B-cell aplasia [1], manageable with regular immunoglobulin infusion, the cytokine release syndrome (CRS) [11], which represents a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms until hypoxemia, hypotension and multi-organ dysfunctions. In most severe cases, the CRS should be treated with anti-receptor-specific antibody of interleukin 6, such as tocilizumab. In addition, neurological symptoms [1,12], whose gravity is quite variable until fatal neurotoxicity, is due to endothelial activation and multifocal vascular disruption, potentially leading to capillary leak and increased blood–brain barrier permeability until intracranial edema [12]. In the ELIANA study, the reported safety profile was in line with previous clinical experiences reported in this setting. Indeed, CRS was observed in 78% of patients, requiring 49% of them the use of tocilizumab. In addition, neurologic toxicities of grade 3 or 4 were observed in 18% of treated patients without any fatalities [3]. In summary, the preliminary data of ELIANA study showed an unprecedented high rate of CR by tisagenlecleucel, providing the basis for its FDA approval (30 August 2017). In addition to promising results achieved in the field of advanced B-ALL, CAR T-cell therapy has been shown to successfully treat refractory B-cell NHLs who have not responded to standard therapies [4,13]. A phase 2 trial (ZUMA-1) [4] of 111 R/R B-cell NHLs patients at 22 medical institutions reported significant results which represented the basis for the approval (18 October 2017) of axicabtagene ciloleucel. In this study, CAR T-cells were successfully engineered for 110 (99%) out of 111 enrolled patients. Of 101 (91%) patients who received the infusion of CTL019 cells, the overall response (OR) and CR rates were of 82% and 54%, respectively [4]; responses were associated with the higher CAR T-cell levels in blood. Noteworthy, 42% of patients maintained a stable response and 40% of them continued to have a CR after a median follow-up of 15.4 months, with a 52% overall survival at 18 months. Similarly, another study [14] reported among 28 R/R B-cell NHLs patients OR and CR rates of 64% and 57%, respectively. Severe CRS (13–18%) and neurologic toxicities (11–28%) were reported in both studies. In addition, manageable myelosuppression were reported in most patients. Finally, four patients died (three in the ZUMA-1 study) [4,14]. In summary, axicabtagene ciloleucel [4] provided a high rate of durable response with a safety profile including the well-known toxicities associated with CAR T-cell therapy [11,12] in R/R NHLs patients without any chance of other effective treatments.

2. Conclusion

The impressive clinical results by tisagenlecleucel and axicabtagene ciloleucel and their FDA approvals represent a milestone in the evolution of adoptive cellular immunotherapy and should be considered promising in view of confirming studies in a real-life population [1,2]. In particular, the management of toxicities and the optimization of supportive measures are critical issues concerning CAR-T cell therapy [11–13]. On the other hand, a large-scale application should be at present considered too difficult, being applicable in selected clinical institutions, provided of transplantation-capable medical centers [2,13] and teams of immunotherapy experts. No less important, the current high costs may preclude the treatment to an elevated number of patients [13,15] and only clinical results in the real life and cost reduction due to technological developments will provide the proper placement of these innovative treatments in the therapeutic algorithm of HM. At the moment, despite the extreme interest in all new forms of innovative therapies, the optimization of available treatments will continue to represent the daily challenge of clinical hematology [5–9].

3. Expert opinion

Although the use of new agents to manage HM has resulted in significant improvements in patient outcomes, treatment resistance as well as R/R disease remained an inevitable challenge. Over the past decade, cell-based immunotherapy has demonstrated to be a promising, effective, and feasible therapeutic tool against several B-cell malignancies. CAR-T is an innovative treatment strategy having the potential of offering an effective salvage and, at the same time, definitive therapy for some B-cell malignancies with a predictable poor outcome, such as those in advanced stage of disease or refractory to standard measures. A ‘one time and forever’ treatment for incurable blood-related disorders is the ultimate goal of CAR-T therapy, recently entered in the therapeutic armamentarium for certain patients with R/R B-ALL and B-cell NHLs, hopefully becoming part of the available measures for a larger population of affected individuals, provided the optimal management of potential toxicities and the drastic cost reduction [15]. In addition, the uniqueness of these treatments, which represent the extreme side of personalized medicine, requires the solution of several problems related to their use in common clinical practice and a redefinition of the rules for the introduction of CAR-T compared to conventional treatments. In the first place, it seems difficult to perform randomized studies involving CAR-T medical products compared to other treatments. Second, although phase II studies have demonstrated the feasibility of cellular therapies based on CAR-T and the possible solution of logistical problems related to their use [3,4,14], the problem of cost containment seems very difficult to cope. Differently from how it has historically happened for other medical treatments, the economic burden unlikely may tend to shrink, even if the application of CAR-T will be proposed on a large scale [13,15]. These concerns may have impact both in ethical terms, such as the fairness to access effective care for patients with the same disease status, as well as the cost sustainability by different health systems of different countries. Further improvement of CAR-T technology as well as the desirable cost containment could lead to a wider adoption of the CAR-T technology by an increasing number of clinical centers in order to offer an effective salvage treatment strategy to a larger population of poor prognosis patients otherwise destined to succumb to their illness. While the results of studies on R/R B-cell malignancies will lead to optimization and an ever wider application of this therapeutic measure to affected patients, further research efforts are expected in the field of myeloid neoplasm. Finally, combination strategies between adoptive CAR-T treatment and other noncellular immunotherapeutic agents [7,8] as well as conventional measures should be the subject of future studies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded