ASH 2019: How can CAR T-cell developers ensure differentiation in NHL?

Commercial availability of two anti-CD19 CAR T-cell therapies (Kite/Gilead’s Yescarta and Novartis’ Kymriah) has revolutionized treatment of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). To date, the efficacy of these novel therapies has been impressive, but severe side effects, logistical hurdles, and reimbursement delays have hindered delivery of these personalized treatments to patients with high unmet need.

Juno/Celgene’s (now BMS’) lisocabtagene maraleucel (liso-cel; JCAR017) is a defined composition anti-CD19 CAR T-cell therapy and the third CAR T-cell therapy poised to enter the DLBCL market. Below, we review the pivotal data reported from the Phase I TRANSCEND NHL-001 study in patients with heavily pretreated DLBCL at the 2019 American Society of Hematology (ASH) conference, summarizing how liso-cel weighs up against current competitors, how it may potentially differentiate itself in this competitive space, and strategic implications for drug developers.

Liso-cel struggles to firmly differentiate on efficacy, however improved safety and potential for outpatient administration will be key

The TRANSCEND NHL-001 dataset depicted below demonstrates that liso-cel’s efficacy is broadly comparable to the currently available CAR T-cell therapies (particularly Yescarta), although response rates are markedly higher than Kymriah’s in the JULIET study. Cross-trial comparison between CAR T-cell studies remains exceptionally challenging due to differences in patient selection (e.g., prior transplantation status) and trial design (e.g., use of bridging chemotherapy).

Going forward, the key comparison for liso-cel will be Yescarta, where two-year outcomes from the ZUMA-1 trial demonstrate that median OS has not been reached. Overall, longer-term follow-up, and real-world use will be important to assess response durability and tease out further differences between the products. In terms of safety, liso-cel continues to impress and this is likely to be a critical differentiator going forward. In TRANSCEND NHL-001, although four treatment-related deaths occurred, rates of severe CRS and neurotoxicity are notably lower than for the other CAR T-cell therapies.

Key efficacy and safety outcomes of anti-CD19 CAR T-cell therapies in R/R DLBCL

Key Efficacy/Safety outcome Yescarta1 Kymriah2 Liso-cel3
ORR 83% 52% 73%
CR 58% 40% 53%
Median PFS (all patients) 5.9 months 6.8 months
Median OS (all patients) NR 12 months 19.9 months
Grade ≥3 CRS 11% 22% 2%
Grade ≥3 Neurological events 32% 12% 10%
Abbreviations: CR = complete response; CRS = cytokine release syndrome; NR = not reached; ORR = objective response rate (Yescarta and liso-cel); ORR = overall response rate (Kymriah); PFS = progression-free survival; OS = overall survival 


When it comes to CAR T-cell treatment in an aggressive cancer such as DLBCL, manufacturing will remain in the spotlight, with any logistical setbacks potentially compromising patient lives. In this regard, Kite/Gilead have experienced the most success with low manufacturing failure rates in ZUMA-1, and Novartis reporting higher rates of manufacturing failure.

In TRANSCEND NHL-001, out of 342 patients that were leukapheresed, 268 patients received liso-cel. Importantly, two patients did not receive the product due to manufacturing setbacks, and a further 24 patients received nonconforming product which may be related to challenges in achieving a defined 1:1 ratio of CD4+/CD8+ T cells. Median vein-to-vein (manufacturing turnaround) time for liso-cel was reported as 24 days, which contrasts with the median turnaround time of 17 days for Yescarta4, and 22 days for Kymriah.5

Despite longer and potentially more complex manufacturing, Juno/Celgene are aiming to make inroads by advancing liso-cel to the outpatient setting, which will ultimately improve patient access. In TRANSCEND NHL-001, just under 10% of patients were administered liso-cel in the outpatient setting, and the company are pursuing this approach in the TRANSCEND-OUTREACH study.6

What does the future hold for liso-cel and other autologous CAR T-cell therapies in DLBCL?

Durable responses will be important but not the sole differentiator. Safety and potential for outpatient administration will become a key focus; the safest product will be well-placed for outpatient use, improving patient access. Physician familiarity and experience will also continue to be key drivers of uptake in the real-world setting.

Manufacturing reliability as well as turnaround time will be pivotal. Given the urgency to treat patients with rapidly progressive disease, and initial setbacks encountered with manufacturing Kymriah, if one product offers significant logistical benefits, it will undoubtedly gain a competitive edge in the long-term.

Cost and improving patient access will be key. In 2019, CMS’ finalized the decision to cover approved CAR T-cell therapies among recipients of Medicare benefits, which will further drive uptake of these expensive therapies in the United States.

Fierce competition within and between therapy classes. Liso-cel and other CAR T-cell therapies are now facing competition from other recently approved targeted agents in DLBCL (Roche’s Polivy) or those in pipeline development (e.g. MorphoSys’ tafasitamab) that have shown promising outcomes and hold clear logistical advantages for patients.

Despite increased competition in the market, DRG expect anti-CD19 CAR T-cell therapies to remain a leading therapy class in DLBCL and garner close to $2.3 billion in major market sales by 2028 in this NHL subtype alone. Anticipated label expansions to the second-line setting will be a predominant driver of sales.

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As CAR T-cell therapies continue to secure approval and increased uptake in DLBCL and other indications, drug developers should explore the following strategic considerations: 

  • What will CAR T-cell developers need to do to ensure successful clinical and commercial differentiation in this competitive space?
  • To what extent will safety and potential for outpatient use drive the potential uptake of liso-cel versus other CAR T-cell therapies?
  • What impact will the availability of novel targeted agents (e.g. Roche’s Polivy) have on the uptake of CAR T-cell therapies as physicians opt for alternatives?
  • What other novel strategies may hold promise and eventually sideline autologous CAR T-cell therapies? (e.g. bispecific antibodies or next-generation allogeneic CAR T-cell approaches?)


  1.  Locke FL et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42.
  2. Schuster SJ et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56.
  3. Abramson JS et al. Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas. 2019 Annual ASH Meeting. Abstract #241.
  4. Yescarta® HCP Product Information 2019 (accessed December 2019).
  5. Kymriah® (tisagenlecleucel) suspension for intravenous infusion: Fact Sheet (accessed December 2019).
  6. A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting (TRANSCEND – OUTREACH) (accessed December 2019).