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Page 10 of 14 Haydu et al. J Cancer Metastasis Treat 2021;7:36 https://dx.doi.org/10.20517/2394-4722.2021.39

secondary CNS lymphoma and of the 6 evaluable patients, the ORR and CR rates were both 50%, compared
[9]
to rates of 73% and 53%, respectively, for patients without secondary CNS lymphoma . No CNS lymphoma
patients had severe CRS, and only 2/6 patients (33%) experienced neurologic events (both grade 3). A
retrospective analysis of 8 patients with secondary CNS lymphoma treated with tisa-cel showed a response
rate of 50% (4/8 patients; 2 CR and 2 PR at day 28), and no patients experienced greater than grade 1
[49]
neurotoxicity . Similar efficacy rates and side effect profiles have been documented in small series of
secondary CNS lymphoma patients treated with axi-cel [50-52] . These data, albeit with relatively small
numbers, provide evidence of anti-tumor activity without significant rates of toxicity and may open new
treatment options for patients with historically dismal prognoses.

Building upon the biologic rationale for CAR T-cell activity in secondary CNS lymphoma, studies are
ongoing to assess CAR T in primary CNS lymphoma, including an ongoing prospective pilot trial
evaluating the safety and efficacy of tisa-cel (NCT04134117) and an ongoing phase 1 trial of an autologous
CD19 specific, hinge-optimized CD28 costimulatory CAR construct generated by the City of Hope (which
also includes secondary CNS lymphoma) .
[53]
Initial CD19 CAR T trials have focused on patients with DLBCL and other relatively common lymphomas.
The TRANSCEND trial did include some rarer lymphomas including grade 3B FL, lymphomas
[9]
transformed from indolent histologies other than FL, and secondary CNS lymphoma, and while liso-cel
showed activity in a proportion of these patients, the relatively small numbers make subset analyses
statistically challenging. In the future, a basket approach combining multiple rare lymphoma subtypes in a
single trial may allow insight into CAR T activity in these diseases and potentially lead to expanded CAR T-
cell indications.

CAR T “plus” combinations
An ongoing question in the field is whether combining agents with CAR T will improve response rates and
durations without contributing additional toxicity. Multiple studies are underway to interrogate CAR T in
combination with immune checkpoint blockade, including ZUMA-6 (atezolizumab following axi-cel in
[54]
refractory DLBCL; NCT02926833) , PORTIA (pembrolizumab following tisa-cel in relapsed/refractory
DLBCL; NCT03630159) , and PLATFORM (durvalumab following liso-cel in relapsed/refractory
[55]
aggressive B-cell NHL; NCT03310619). PLATFORM is also exploring liso-cel in combination with the
immunomodulators CC-122 and CC-220.

Preclinical studies have shown that the BTKi ibrutinib improves CAR T-cell function, quality, and anti-
tumor responses [56,57] , suggesting that BTKi in combination with CAR T might lead to improved outcomes.
All patients treated with axi-cel in ZUMA-2 and with liso-cel in the TRANSCEND CLL cohort had
[43]
[12]
prior BTKi exposure by eligibility criteria, as did 88% of patients treated with liso-cel in the TRANSCEND
MCL cohort , and some patients were also bridged with BTKi, and thus BTKi exposure might have led to
[25]
immune system changes that contributed to CAR T responses. Several ongoing studies are addressing
BTKi/CAR T combinations, including tisa-cel with ibrutinib in relapsed/refractory DLBCL (NCT03876028),
a CD19 CAR T construct with ibrutinib in relapsed/refractory CLL (NCT01865617) , and liso-cel with
[58]
[59]
ibrutinib for relapsed/refractory CLL [PLATFORM (NCT03310619) and TRANSCEND (NCT03331198) ].
In a recent interim analysis, liso-cel with ibrutinib led to an ORR of 95% (18/19 CLL patients) with a
CR/CRi in 47% (9/19) of patients with greater than 1 month of follow up, and relatively low rates of CAR T-
associated toxicities . In the trial with a CD19 CAR T construct, the ORR at 1 month was 83% (15/18
[59]
evaluable CLL patients), with a 1-year OS of 86% and PFS of 59%, and a lower severity of CRS in patients
treated with CAR T-cells with ibrutinib compared to those patients not given concurrent ibrutinib .
[58]