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Page 12 of 19 Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05

CAR T-cell therapy
In the last years, anti-CD19 Chimeric antigen receptor (CAR) T-cell therapy proved to be a valuable
addition to the therapeutic armamentarium of R/R acute lymphoblastic leukemia and DLBCL. More
recently, this treatment strategy has shown promising results in the setting of indolent B-cell lymphomas.
The phase II ZUMA-5 study, for instance, has explored the efficacy and safety of axicabtagene ciloleucel
(axi-cel) in R/R FL and MZL. Among 124 patients with FL, 84 were evaluable for efficacy: ORR was 94%
with 80% of patients achieving a CR; the 12-month PFS and OS were 74% and 93%, respectively, while
[98]
median OS was not reached . The most common AEs related to CAR T-cell therapy, namely CRS and
immune effector cell-associated neurotoxicity syndrome (ICANS), were experienced by 77% and 55% of
[98]
patients, respectively. However, only 6% CRS and 15% ICANS were considered Grade ≥ 3 . Based on these
results, axi-cel has received FDA approval for the treatment of R/R FL after two or more lines of therapy,
adding to its indication for R/R DLBCL. Another phase I/II trial has confirmed the efficacy of anti-CD19
CAR T-cells in FL, testing a second-generation CAR, with 4-1BB co-stimulation and formulated at 1:1
CD4+:CD8+ CAR T-cell ratio . The study enrolled eight patients with FL, seven of whom responded, all of
[99]
them obtaining a CR (88%). All responding patients remained in CR for a median follow-up of 24 months,
with remissions lasting up to three years after CAR T-cell infusion. No Grade ≥ 3 CRS or ICANS was
[99]
registered .

Bispecific monoclonal antibodies
In the 1960s, some researchers demonstrated the possibility of combining two different univalent Fab’
fragments into a bivalent antibody construct harboring specificity for two different antigens . Bispecific
[100]
antibodies (BsAbs) are single polypeptides comprised of two different monospecific antigen-binding
regions: one of the binding sites recognizes the neoplastic cell, while the other part binds T or natural killer
(NK) cells. The BsAbs employed in B-cell neoplasms generally recognize tumor cells through an anti-CD20
or anti-CD19 binding region, while the other site binds to T-cells through the CD3 surface antigen . This
[100]
leads to recruitment, activation, and expansion of T lymphocytes in an MHC-independent way; effector
cells can then direct their cytotoxicity against the malignant cells expressing the target antigen. Four
CD20/CD3 BsAbs constructs are currently being studied for the treatment of FL: odronextamab,
mosunetuzumab, glofitamab, and epcoritamab.

Odronextamab is a first-in-class, intravenously administered, human IgG4-base BsAb. The FL patients
enrolled in the phase I study obtained a 93% ORR with 75% CRR; mPFS was 12.8 months . CRS was one
[101]
of the most frequent AEs and was reported to be Grade ≥ 3 in 11% of cases. A phase II study is ongoing to
confirm the role of odronextamab in NHL, including 112 patients with FL (NCT03888105).

Mosunetuzumab is a fully humanized IgG1 BsAb, which has received FDA breakthrough designation for
R/R FL. The drug, which is given intravenously, achieved a 68% ORR with 50% CRR on 62 FL patients
treated in a phase I/Ib study. The results were consistent among all high-risk groups. Median DOR and
mPFS were 20 and 11.8 months, respectively; among patients obtaining a CR, 74% are still in remission. The
safety profile proved to be favorable, with neutropenia as the most common AE, and only 23% of patients
experienced CRS (of which only 1.6% were considered to be serious AEs) . The drug is also being studied
[102]
in a subcutaneous formulation, which seems to be associated with an even lower rate of relevant AEs,
namely Grade 2 CRS and neurologic toxicity . The results reported by Matasar and colleagues show an
[103]
86% ORR with CRR of 29% in the indolent NHL subgroup .
[103]

Epcoritamab is a humanized mouse IgG1-based heterodimeric antibody, which is currently undergoing
evaluation in a phase I/II trial in R/R NHL patients, including 12 patients with FL (NCT03625037). The