With the FDA's approval of two CD19-targeted CAR-T cell products — Yescarta and Kymriah — as third- or more lines of therapy for relapsed and/or refractory large B-cell lymphomas, this type of cancer has entered an exciting new era of targeted anticancer therapy.
In December last year, two-year data from the pivotal clinical trial ZUMA-1 on Yescarta were published in The Lancet Oncology .A preliminary report on Kymriah's pivotal clinical trial, JULIET, was also presented at NEJM in January .
Picture source: The Lancet Oncology
ZUMA-1 enrolled 119 patients between 19-May-2015 and 15-Sep-2016, 108 of whom received Yescarta reinfusion.As of 11 August 2018, a median of 27.1 months of follow-up has been conducted for the 101 patients evaluable in the Phase II trial.The objective response rate was 83%, with a CR rate of 58%.The median duration of response was 11.1 months.Median overall survival was not reached and median progression-free survival was 5.9 months.Of the 108 evaluable patients in Phase I and Phase II, 48% had Grade ≥ 3 serious adverse events: 11% had Grade ≥ 3 cytokine release syndrome (CRS), and 32% had Grade ≥ 3 neurotoxicity.With the exception of two previously reported cases, no new treatment-related deaths occurred during follow-up.
Picture source: NEJM
In the JULIE trial, a total of 93 patients were reinfused with Kymriah and included in the efficacy assessment.The median time from reinfusion to data cutoff was 14 months.The overall response rate was 52%, with 40% CR and 12% PR.Response rates were consistent across prognostic subgroups.After 12 months from initial response, recurrence-free survival was estimated at 65%, with 79% of patients in CR.The most common Grade 3 or 4 specific adverse events included CRS (22%).Neurotoxicity (12%).Pancytopenia lasting more than 28 days (32%).Infections (20%) and febrile neutropenia (14%).Three patients died within 30 days of reinfusion due to disease progression.No deaths were reported by Kymriah.Caused by CRS or cerebral edema.
Image source: Nature Reviews Clinical Oncology
On February 27, a University of Washington scientist published an article in Nature Reviews Clinical Oncology titled "Anti-CD19CAR T cell therapy for lymphoma-off to the races!"The author made a detailed comparative analysis of these two CAR-T products.
The article states that these two multicenter.Single-arm trials have shown that patients receiving CD19-CAR-T therapy have a high response rate and survival exceeds the "historical record" (this record is the median survival of 6.2 months, from the retrospective SCHOLAR-1 analysis of patients with refractory diffuse large B-cell lymphoma).
Both trials enrolled patients with diffuse large B-cell lymphoma (DLBCL) and patients with DLBCL transformed from follicular lymphoma or other high-grade B-cell lymphomas.However, ZUMA-1 also enrolled patients with primary mediastinal B-cell lymphoma, which JULIET did not involve.
Although there are many similarities, the specific operations in clinical trials and the differences between the two CAR-T cell products prevent a direct comparison between the data.
Treatment Method Comparison
Both products are generated from autologous CD3 + T cells collected by leukapheresis and shipped unfrozen to the manufacturer.Kymriah is shipped to the manufacturer after cryopreservation.
Yescarta uses retroviral vectors and Kymriah uses lentiviral vectors.
Yescarta was administered at 2 × 106 cells/kg, while Kymriah was administered at doses ranging from 0.1 – 6.0 × 108 cells (median 3.0 × 108 cells).
CAR-T cells are usually returned to the patient after chemotherapy.The effect of chemotherapy is to eliminate the endogenous T cells and increase the survival rate of CAR-T cells.At the same time, it also reduced or delayed the immune rejection of CAR-T cells.
In ZUMA-1, chemotherapy doses were higher: 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine per day for 3 days.In JULIET, chemotherapy doses were: 250 mg/m2 cyclophosphamide and 25 mg/m2 fludarabine per day for 3 days.In addition, in JULIET, chemotherapy was omitted in patients with severe cytoreduction (7%) and some patients received bendamustine.Differences in chemotherapy may affect early overall response rates but are unlikely to affect long-term complete response rates.
Design of CAR-T cells (Source: Nature Reviews ClinicalOncology) 
The CAR constructs of Yescarta and Kymriah contain the same CD19 targeting domain (CD19-targeting domain) as well as the CD3ζ signaling domain, but differ in the costimulatory domain, the former being CD28 and the latter 4-1BB.The CD28 costimulatory domain was associated with an earlier peak of T-cell expansion than the 4-1BB costimulatory domain, which may explain why Yescarta treatment was associated with an earlier onset of toxicity.In ZUMA-1, the median time to onset of CRS (any grade included) was 2 days, whereas in JULIET, the corresponding time was 3 days.Earlier onset of toxicity with Yescarta treatment requires hospitalization.
CRS is associated with cell proliferation and cytokine production, which can be controlled in part by blocking the IL-6 receptor with tocilizumab or corticosteroids alone.
Neurotoxicity is another, sometimes life-threatening, but poorly understood adverse effect of CD19-CAR-T therapy, which usually follows CRS and is also controlled with corticosteroids.
Because of the different grading systems used in ZUMA-1 and JULIET, it is not easy to compare the toxic side effects observed in these two trials.
In ZUMA-1, according to the revised version of the grading criteria proposed by Lee et al. , grade ≥ 3 CRS occurred in 11% of patients, and grade ≥ 3 neurotoxicity occurred in 32% of patients.
In JULIET, the investigators used the University of Pennsylvania grading scale, and 22% of patients experienced grade ≥ 3 CRS and 12% experienced grade ≥ 3 neurotoxicity.If the toxicity in JULIET was reclassified according to the grading criteria proposed by Lee et al., the incidence of CRS ≥ grade 3 was reduced to 17%.
Although the frequency of severe CRS was similar, Yescarta was associated with a higher overall incidence of CRS and more frequent use of tocilizumab than Kymriah.
Image source: Nature Reviews Clinical Oncology
In terms of response, Yescarta and Kymriah were associated with 58% and 40% complete responses, respectively, in patients with a poor prognosis.Objective response may occur after 4 weeks of treatment.In the following months, many patients will relapse.However, in patients who do not relapse, the response will continue to increase over the next few months.Patients who achieve complete remission at 3-6 months have a lower risk of relapse.
ZUMA-1 showed that nearly 40% of patients treated with Yescarta remained in remission after a median follow-up of 2 years, with few late relapses, suggesting that many of these patients may be cured.
In the ZUMA-1 trial, patients who received CAR-T cell reinfusion, median overall survival ampgt.2 years.In the JULIET trial, the corresponding data were ~ 1 year.
When treated with Yescarta, expansion of CAR-T cells in the first 28 days (peak concentration in blood) as well as total exposure (cumulative concentration) were associated with sustained remission.However, this association was not observed with treatment with Kymriah, nor was there an association between dose and response.
Comparing these efficacy data suggests that Yescarta is more effective than Kymriah, but the design of clinical trials and eligibility criteria for both make it more complicated to determine who is better.
Apheresis: A technique in which the patient's blood is passed through a device that separates a specific component and returns the remainder to the body.(Source: Wikipedia)
In ZUMA-1, because "bridging chemotherapy" is not allowed, only patients who can wait for a certain cell production cycle can be selected, and the median period from apheresis to making CAR-T products is 17 days.In JULIET, patients are recruited at the time of apheresis, but wait ~ 54 days from apheresis to reinfusion of CAR-T cells for treatment.Therefore, 92% of patients required "bridging chemotherapy" to control their condition, and a significant number of patients received apheresis but did not wait for CAR-T reinfusion (some died while waiting, and some did not meet the conditions for continued treatment).
The likelihood of long-term remission and the risk of severe toxicity appear to be related to disease burden.In ZUMA-1, patients in the lowest quartile of tumor burden had a 1-year response rate of 67%, and the incidence of grade ≥ 3 CRS and neurotoxicity was only 4%, respectively.7%.Among patients in the highest quartile of tumor burden, the three corresponding values were 27%.31% and 12%.Therefore, in clinical practice, treatment before patients develop refractory disease may improve outcomes.
In summary, data from the ZUMA-1 and JULIET trials indicate that CD19-targeted CAR-T cell therapy provides durable responses in 30 – 40% of patients with relapsed and/or refractory aggressive large B-cell lymphoma with a low risk of disease recurrence or progression.Two-year follow-up of ZUMA-1 did not reveal any unexpected toxicity, but further safety monitoring is needed.
However, despite the impressive results of the ZUMA-1 and JULIET trials, there is still much room for CD19-CAR-T therapy to improve durable remission rates and reduce toxicity, the authors note.
In addition to these two products, the results of a clinical trial of a CD19 – 4-1BB CAR-T cell product called lisocabtagene maraleucel (administered at a specific CD4 + T cell/CD8 + T cell ratio) showed encouraging results, with lower rates of CRS and neurotoxicity observed in the trial than in ZUMA-1 and JULIET.
The authors concluded that in the future, the same toxicity criteria should be used in CAR-T cell assays to enable cross-trial comparisons.In this regard, the American Society for Blood and Marrow Transplantation grading criteria for CRS and neurotoxicity are currently available.In addition, ideally, the protocols for cell collection should be improved so that the collection of lymphocytes can be done in more places than focused on a specific manufacturer.
Ultimately, the commercial acceptance of these products will depend on clinical efficacy.Safety and health care costs, including drug costs.Outpatient or inpatient management fees.Length of hospital stay and time spent in the ICU due to serious adverse reactions.
1] FrederickL Locke et al.Long-term safety and activity of axicabtagene ciloleucel infracyclic large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1 – 2 trial.The Lancet Oncology (2018).
2] StephenJ.Schuster etal.Tisagenlecleucel in Adult Relapsed or Refractive Diffuse Large B-CellLymphoma.NEJM (2019).
3] HollieJ.Jackson etal.Driving CAR T-cells forward.Nature Reviews Clinical Oncology (2016).
4] Lee, D.W. et al.Current concepts in the diagnosis and management of cytokine release syndrome.Blood (2014).
1anti-CD19 CAR Tcelltherapy for lymphoma-off to the races!