Overview of approved CAR‐T therapies, ongoing clinical trials, and its impact on clinical practice

Abstract In recent years, we have seen rapid expansion of chimeric antigen receptor T‐cell (CAR‐T) therapies in multiple malignancies. CAR‐T therapy has profoundly altered the treatment landscape of non‐Hodgkin lymphoma, B‐cell acute lymphoblastic leukemia, and multiple myeloma. Currently available CD19 and B‐cell maturation antigen‐directed CAR‐T therapies have shown high overall response rate and durable remissions in patients who have failed standard therapies. Multiple studies are underway exploring the role of CAR‐T‐cell therapy as earlier line of treatment. In high‐grade B‐cell lymphoma, CD19 CAR‐T therapy may replace autologous hematopoietic cell transplantation as second line therapy in near future. CAR‐T‐cell therapy targeting novel tumor‐associated antigens will help expand utility of this treatment modality in other hematological malignancies. It may also help overcome limitations of currently approved CAR‐T‐cell therapies. In this review, we have provided an overview of currently approved CAR‐T therapies and upcoming clinical trials which may potentially impact the clinical practice.

reported in the initial ZUMA-1 trial, and no new treatment-related adverse events were subsequently reported. These follow-up data confirmed that axicabtagene ciloleucel induced durable responses with a median OS greater than 2 years and a very well tolerated long-term safety profile [3].
In the real-life application of axi-cel as standard of care (SOC), additional outcomes data from US Lymphoma CART consortium, which is a group of 17 US institutions, showed that SOC axi-cel outcomes were comparable to trial data for R/R HGBCL. This retrospective study included 275 patients who received axi-cel, despite many of these patients (43%) would not have met eligibility criteria of ZUMA-1 trial to comorbidities. Best ORR and CR rates were 82% and 64%, respectively, with comparable rates of CRS and ICANS as in ZUMA-1. Median PFS was 8.3 months, and OS had not yet been reached. They did discern that patients with Eastern Cooperative Oncology Group (ECOG) performance status of 2-4 and elevated LDH had reduced PFS and OS in this study but overall, the response rates, CR rates, and toxicity rates, particularly of CRS and ICANS were similar to the ZUMA-1 trials [4].
Axi-cel received its second indication on March 5, 2021, when it received accelerated FDA approval for patients with R/R FL after two or more lines of therapy. The approval was based on the ZUMA-5 study (NCT03105336) which was a single arm, open label study of 81 patients with R/R FL or marginal zone lymphoma (MZL). The results showed an ORR of 92% with 76% of patients still in continued remission after 18 months. The median duration of response had not been reached yet. Grades 3 or higher CRS and ICANS were 8% and 21%, respectively. This approval set the stage for the first approval for an indolent lymphoma, meeting an unmet need of relapsed refractory indolent lymphomas of which survival in the R/R setting is only 20% at 5 years [5].

TISAGENLECLEUCEL
Tisa-cel was first reported in a study of pediatric patients and young

LISOCABTAGENE MARALEUCEL
On February 5, 2021, liso-cel became the third CD19-targeted CAR-T product to be FDA approved for R/R HGBCL. This approval was based on the TRANSCEND trial which was a single arm multicenter trial for patients with R/R large B cell lymphoma who had received at least two lines or more of therapy. This study included 192 patients with a reported ORR of 73% with CR rate of 54%. Of the patients who achieved CR, 65% of those patients, or approximately two thirds, had remissions lasting at least 6-9 months. Grades 3 or higher CRS and ICANS occurred in 4% and 12% of patients, respectively. Other significant adverse events included cytopenias and infection [9].

BREXUCABTAGENE AUTOLEUCEL
Brexu-cel is the first anti-CD19 CAR-T cell therapy approved for/R MCL. In a multicenter single arm study that included 60 patients with R/R MCL who had received a bruton tyrosine kinase (BTK) inhibitor, anthracycline-or bendamustine-based chemotherapy, and CD 20 monoclonal antibody, impressive results were seen in patients who received a single dose of brexu-cel with reported 93% ORR and 67% CR rate in this study. At 12-month follow-up, PFS and OS were 61% and 83%, respectively. Grades 3 or higher CRS and ICANS events were seen at the rate of 15% and 31% respectively; none of which were fatal. As with other CAR-T studies, additional serious reported adverse events were cytopenias and infections [10]. Despite the high ORR and CR rates with brexu-cel, data suggest that those patients who relapse after CAR-T therapy have dismal outcomes [11].  [16]. Similar results have been announced using liso-cel is a second line therapy for HGBCL in another phase 3 study (TRANS-FORM, NCT03575351) [17]. Contrary to these two trials, a comparable phase 3 trial (BELINDA, NCT03570892) using tisa-cel failed to meet the primary endpoint [18]. CAR-T therapies targeting CD123 and NKG2D have shown some efficacy in relapsed acute myeloid leukemia (AML) [21,22]. In a phase I/II study, CD30-directed CAR-T-cell therapy showed ORR of 72% and CR rate of 59% in R/R Hodgkin lymphoma with an excellent safety profile [23]. T cell malignancies are inherently difficult to target with CAR-Tcell therapy due to morbidity associated with prolonged T cell aplasia and limited in vivo expansion due to fratricide. Multiple ongoing studies are testing safety and efficacy of CD5, CD7, CD4 -directed CAR-T in R/R T cell lymphoma, and T cell ALL. In a phase I study, Pan et al.
showed high CR rate with manageable safety profile of donor-derived CD7 CAR-T cell in R/R T-ALL [24]. This approach led to higher rates of MRD clearance compared to CAR-T-cell therapy alone [25]. Similar approach has been described in patients with R/R NHL, where repeat infusion of CD19 CAR-T-cell therapy after pretreatment with ibrutinib led to better in vivo expansion of CAR-T cells and disease responses [26]. The preliminary analysis of ZUMA-6 (NCT02926833) showed that the combination of atezolizumab (anti-PD-L1 monoclonal antibody) with axi-cel was safe, but ORR and CR were comparable to single agent axi-cel in patients with R/R HGBCL [27]. In MM space, multiple studies are ongoing combining BCMA-CAR-T with IMiD or anti-CD38 monoclonal antibody [28].

Impact of CART on clinical practice
CART has had significant impact and changed the paradigm for the treatment of large B cell lymphoma, FL, marginal zone lymphoma, MCL, and ALL [9,29,30].
Patients with relapse or refractory HGBCL have a particularly poor prognosis as the likelihood of response to salvage chemotherapy is 26%, and medial OS is 6 months. Many of these patients end up going from one toxic chemotherapy to another and getting sicker and sicker until they go on palliative care or hospice. However, with the advent of axi-cel, this same patient population now has an ORR of 84%, CR rate of 59%, and median OS at 2 years not reached [3]. Tisacel also had high response rate of 52% and 1-year relapse-free survival of 65% [30]. Taken  Unlike chemotherapy that is given as multiple cycles over many months, CART is a single infusion in most cases. In HGBCL, responders to CART do not need maintenance therapy. This allows them to spend more time away from oncology and more time in the community. Practices will adjust to this new follow-up pattern.
CART have changed the pattern of clinical practice in that we are having much fewer referrals to hospice and end of life care because more patients who received CARTs achieve complete and durable response compared to chemotherapy alone. CART patients use hospital bed earlier in the treatment process during the active phase of monitoring for and treating higher grade acute toxicities including CRS and neurological complications. Hospital bed use after this time is rare.
High-volume CAR-T centers are developing expertise to manage CAR-T-treated patients in the outpatient settings. This will allow significant cost-savings and better quality of life.
In summary, CART therapy is new and during the past few years has become firmly embedded in the treatment of HGBCL, FL, MZL, and B-ALL. As it is becoming more popular and able to be used in earlier lines of therapy, the paradigm and our practice pattern will continue to adapt to this new reality. As the safety profile improves and CARTs able to be given in centers that are not necessarily tertiary centers of excellence, practice patterns will continue to change to manage new toxicities and accommodate the improved survival across the board.