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The introduction of immunotherapies has transformed the treatment paradigm for hematological malignancies such as non-Hodgkin lymphoma (NHL).1 Both antibody- and cell-based immunotherapies are available in NHL,2 and this feature will focus on two emerging examples discussed at iwNHL 2022: CAR-T therapy – T lymphocytes genetically engineered to express an artificial receptor that directs them against a specific tumor antigen;3 and bispecific T-cell engagers (BiTEs) – bispecific antibodies that simultaneously bind an antigen expressed on tumor cells and a surface molecule on T-cells to induce tumor lysis.4
Autologous CD19-targeted CAR-Ts have been widely used to treat B-cell NHLs.5 It is the more established of the treatment options discussed here, with between 2-5 years of follow up data now available. Key CAR-T therapies in NHL include axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel).
At iwNHL 2022, Jason Westin, MD, of the University of Texas MD Anderson Cancer Center, Houston, TX, noted that among the factors to consider when choosing a therapeutic approach, including toxicity and logistics/feasibility, efficacy is the most important. Key parameters for efficacy include response rates (overall [ORR] and complete [CRR]), duration of response (DOR), and survival measures (overall [OS], event-free [EFS], and progression-free [PFS]).
CAR-T has predominantly been indicated for the relapsed or refractory (R/R) setting. Five-year follow up data from the ZUMA-1 study (NCT02348216) evaluating axi-cel in adults with refractory aggressive NHL treated with more than three prior lines of therapy show an OS of 42.6%, with median OS of 31.0 months, versus 5.4 months for a pre-CAR-T population comparator (SCHOLAR-1).6 Moreover, EFS at 24 months was 37.7%. Dr Westin commented: “38% of patients have not had a progression event7 and we know that that is a powerful predictor for long-term outcomes,” as well as an indication of CAR-T being curative.
Results from other pivotal trials of CAR-Ts can be found in Table 1.
|Trial||Phase||Drug||Length of follow up||Readout|
|ZUMA-5||Phase II||Axi-cel||Median 30.9 and 23.8 months (FL and MZL, respectively)8||Follicular lymphoma (FL) ORR was 94% (79% CR). 57% of patients had ongoing responses; 68% had an ongoing CR. DOR and PFS medians were 38.6 and 39.6 months, respectively. Median time to next treatment (TTNT) was 39.6 months and median OS was not reached.
In marginal zone lymphoma (MZL) patients ORR was 83% (63% CR). 50% of patients had ongoing responses; 73% had ongoing CR. Medians for DOR, TTNT and OS were not reached. Median PFS was 17.3 months.8
|ZUMA-7||Phase III||Axi-cel||Two years||Median EFS 41.0% for axi-cel and 16.0% for standard of care (SOC). Response occurred in 83.0% for axi-cel and 50.0% for SOC (with CRs of 65% and 32%, respectively).9|
|JULIET||Phase II||Tisa-cel||40 months||PFS of 2.9 months. ORR to tisa-cel was 53.0%, with 39.0% having a CR.11|
|ELARA||Phase II||Tisa-cel||Median 16.6 months||Interim data show an ORR of 86.2%, with a CRR of 69.1%.12|
|BELINDA||Phase III||Tisa-cel||Six weeks||Tisa-cel failed to improve EFS versus SOC in patients with aggressive R/R NHL. 13|
|TRANSCEND||Phase I||Liso-cel||Two years||Reported median DOR was 23.1 months (probability at two years: 49.5%), median PFS 6.8 months (40.6%), and median OS 27.3 months (50.5%).14|
Slightly less well-established than CAR-T, BiTEs currently have around 1-2 years of follow-up data available from clinical studies. Key BiTEs include blinatumomab targeting CD19 and CD3; and mosunetuzumab and glofitamab both targeting CD20 and CD3.
Results from pivotal studies for BiTEs are outlined in Table 2.
|Trial||Phase||Drug||Length of follow up||Readout|
|NCT03075696||Phase I/II||Glofitamab||Eight months||In patients who were heavily pre-treated with ≥ three prior treatment lines median PFS was 4.9 months, 12-month EFS 37.1% and median OS 11.5 months, with a 12-month OS rate of 49.8%.15|
|NCT02500407||Phase I/II||Mosunetuzumab||Best ORRs were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, with CRRs of 19.4% and 48.5%. In those with a CR, the median DOR was 22.8 and 20.4 months, respectively.16|
While Dr Subklewe explained that the best responses are comparable with CAR-T, the DOR is still under investigation and, with the length of follow-up currently much shorter for BiTEs than CAR-T, their ability to cure patients is yet to be determined.
T-cell exhaustion was noted by both Dr Westin and Dr Subklewe as a concern for efficacy in both CAR-T and BiTEs. “It has been shown for blinatumomab that certain T-cell subsets and T-cell exhaustions are enriched in patients who are not responding to therapy,” explained Dr Subklewe, noting that dysfunctional T-cells correlate to non-response in both BiTEs and CAR-T. She also described how T-cell fitness is dictated by chemotherapy, with T-cell subsets and T-cell function declining after multiple lines, impacting outcomes such as CRR and PFS, and thus making a case for implementing these treatments earlier in the therapeutic paradigm.
She went on to describe how for BiTEs, dosing must be carefully considered to prevent T-cell exhaustion. “We see a decrease in T-cell proliferation and cytotoxicity upon continuous exposure,” both of which limit efficacy but can be ameliorated with treatment-free intervals, she stated.
Dr Westin explained that there are four primary concerns with CAR-T: toxicity, delivery at specialist centers, the length of manufacture, and challenges when combining with other therapies.
Dr Westin commented on the toxicity of CAR-T, with Grade ≥3 cytokine release syndrome (CRS) toxicities occurring in 0-10% with 4-1BB costimulated CARs and between 10-20% in the CD28 CAR axi-cel. He added: “Neurotoxicities are more common, especially for the CD28 CARs, but you can say that two out of three patients will not have Grade ≥ 3 neurotoxicity and the potential for cure makes that a little bit less daunting.”
In BiTEs, Dr Subklewe presented that, in her experience, dosing has also been an important consideration to mitigate toxicities: “Ramp-up dosing is a great strategy to mitigate CRS and immune-related side effects, and on the same line the subcutaneous administration with a more gradual increase of the bispecific and plasma cytokine levels has shown a really promising safety profile with no higher Grade CRS in cycle 2.” She added that this approach has even shown promising safety in elderly patients aged 80 years and over.
Comparing the rates of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) between trials of CAR-T and BiTEs, Dr Subklewe showed that for CAR-T Grade 3 or higher events were much more frequent. She added that because of their apparent safety, BiTEs are easier to combine with other agents, including two notable examples: glofitamab with R-CHOP17 in both first-line and R/R NHL, and glofitamab and polatuzumab vedotin (Pola) in R/R diffuse large B-cell lymphoma (DLBCL), where both promising safety and response rates have been reported.18
Another comparison made by Dr Subklewe is around manufacturing and availability because while CAR-T may take 90 days from indication to transfusion, BiTEs are an off-the-shelf allogeneic product where patients can be at full dose in 15 days. However, in terms of time to response, both are similar according to Dr Subklewe, and Dr Westin noted only CAR-T is the proven curative option.
Both BiTEs and CAR-T have shown promising outcomes in the R/R NHL setting. However, despite having comparable response rates, entering clinical testing later means BiTEs still require further study on their DOR. Yet it is not necessarily a one or the other situation; each could have their place and even be combined within the treatment paradigm. For instance, Dr Westin noted that BiTEs could be leveraged first for debulking followed by CAR-T for cure, or alternatively utilized where patients are ineligible for CAR-T. Dr Subklewe added: “We have to move away from CAR-centric models… Our task is to identify which patient is going to benefit most from each therapeutic platform.”
In summary, as Dr Westin noted, “CAR-Ts and bispecifics are incredibly powerful therapies that have not yet reached their full potential.”
View Dr Westin’s and Dr Subklewe’s presentations at iwNHL here.
The CAR-T & Cellular Therapy Focus on VJHemOnc is supported by Janssen Pharmaceuticals (a Johnson & Johnson Company) and Legend Biotech.
These supporters have no influence over the production of the content.
iwNHL 2022 was supported by:
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