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Haydu et al. J Cancer Metastasis Treat 2021;7:36 https://dx.doi.org/10.20517/2394-4722.2021.39 Page 9 of 14

months, the median duration of response was not reached, and the median PFS was 18 months. Safety
profiles were similar to what has been seen previously with liso-cel. Interestingly, of the 20 patients
evaluable for minimal residual disease (MRD), 75% (15/20) had undetectable MRD in the blood and 87%
(13/15) also had undetectable MRD in the bone marrow, raising the possibility of CLL/SLL disease
eradication with CAR T approaches.

Bridging patients to CAR T-cell therapies
Bridging patients to CAR T therapy is an area of unmet clinical need. Bridging was permitted in the
[11]
[9]
JULIET and TRANSCEND trials of relapsed/refectory large B-cell lymphomas, with the majority of
patients receiving bridging therapy (92% and 72%, respectively). ZUMA-1 prohibited bridging but most
[10]
patients receiving axi-cel in the real world context have also required bridging therapy . Importantly,
[44]
bridging therapy has been associated with lower response rates and durability, with an ORR of 67.3% for
bridged patients in TRANSCEND compared to 80.2% for non-bridged patients, as well as a higher incidence
of CRS and neurologic events in bridged patients . A retrospective analysis of 298 patients with large B-cell
[9]
lymphoma treated with commercially available axi-cel found that bridging therapy was associated with an
inferior OS (HR = 1.7 in bridged vs. non bridged patients) . The inferior outcomes associated with
[23]
bridging are likely multifactorial and may largely reflect the characteristics of patients who require bridging
therapy: patients with bulkier, more rapidly progressive, and/or symptomatic disease who are likely to have
additional risk factors for inferior outcomes and increased toxicities, including high tumor burden.

Current bridging approaches are not effective in many patients, a perhaps unsurprising observation given
that patients eligible for CAR T therapy have typically had chemotherapy-refractory disease. Importantly, a
significant subset of patients never make it to CAR T-cell infusion in part due to failure of bridging therapy
to control disease, with 54/165 patients in JULIET ultimately not receiving CAR T-cells and death from
[26]
disease progression in 33/344 patients in TRANSCEND . In the brexu-cel relapsed/refractory MCL trial,
[9]
the majority of the bridged patients actually had an increase in median tumor burden by radiographic
imaging over the bridging period , further reflecting the challenging nature of controlling
[12]
relapsed/refractory disease with current bridging techniques and underscoring the need for novel
approaches that maximize efficacy and limit systemic toxicity.

In DLBCL patients awaiting CAR T therapy, bridging has typically been attempted with steroids,
chemoimmunotherapy, and/or radiation. Steroids are a viable bridging option with less systemic toxicity
than chemoimmunotherapy, though responses are often short lived. Radiation is an attractive bridging
modality for localized and/or focally symptomatic disease given the minimal systemic toxicity. Potential
novel bridging approaches include agents which have demonstrated efficacy in relapsed/refractory DLBCL,
including brentuximab vedotin for CD30+ disease , lenalidomide or BTKi for non-GCB disease , and the
[45]
[46]
CD79B antibody drug conjugate polatuzumab vedotin . The anti-CD19 therapy tafastimab has promising
[47]
activity in combination with lenalidomide in relapsed/refractory DLBCL for which it is FDA approved ,
[48]
but the impact of CD19-targeted agents prior to planned anti-CD19 CAR T-cells is unknown, and should be
avoided in the absence of data showing it does not impair the curative potential of subsequent anti-CD19
CAR T-cells.

THE FUTURE OF CAR T
Expanding eligibility
Patients with secondary CNS lymphoma were excluded from the initial axi-cel and tisa-cel trials given the
theoretical concern for CAR T-cell related neurotoxicity but were eligible for liso-cel in TRANSCEND as
long as there was also measurable non-CNS disease. Overall, 7/269 (3%) of patients in TRANSCEND had