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Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05 Page 13 of 19

drug is given subcutaneously. All eight FL patients who received the BsAb at a dose ≥ 0.76 mg obtained an
[104]
objective response (100% ORR) with 25% CRR .
Glofitamab is an intravenously administered, humanized mouse IgG1-based BsAb with a 2:1 configuration:
its CD3-binding region is connected to one of the two CD20-binding regions through a flexible linker, thus
enabling bivalent binding to CD20 on B cells and monovalent binding to CD3 on T-cells. CD20 bivalency
[105]
enhances the potency of glofitamab even in the setting of pre- or co-treatment with anti-CD20 agents .
Moreover, the drug shows a longer half-life compared to the other BsAbs constructs. The phase I study
(NCT03075696) in which the drug was evaluated included 44 patients with FL, who achieved 70.5% ORR
and 47.7% CRR. Responders showed an mDOR of 10.8 months; in particular, 90.5% patients in CR
[105]
remained in remission up to 22.9 months . Toxicities were manageable, with low rates of Grade ≥ 3
CRS .
[105]
Overall, BsAbs display promising results in pre-treated patients with FL, even among high-risk groups,
although their ability to provide sustained remissions similar to those observed after CAR T-cell therapy still
needs to be confirmed. A considerable advantage they have over CAR T-cells is their availability as off-the-
shelf products, as well as not requiring administration of lymphodepleting chemotherapy. Moreover, their
toxicity profile seems much more favorable compared to CAR T-cells, with lower rates of Grade ≥ 3 CRS
and neurotoxicity.

Checkpoint inhibition
Currently, the application of anti-programmed cell death protein (PD) 1 and programmed cell death ligand
(PD-L) 1 to FL is confined to clinical trials, although responses to these agents have been largely reported.

A novel immune checkpoint inhibitor targeting CD47 has recently shown promising results in combination
with rituximab in a phase Ib/II study enrolling patients with FL and DLBCL . CD47 is overexpressed on
[106]
the surface of cancer cells in multiple malignancies and works as a “do not eat me” signal to phagocytic cells.
The binding of the blocking antibody (Hu5F9-G4) to the receptor induces the phagocytosis of lymphoma
cells; their destruction is enhanced by the concomitant exposure to rituximab, which induces complement
and NK cell-mediated, antibody-dependent, cellular cytotoxic effect. Among patients with FL, the ORR was
71% with three patients (43%) obtaining a CR; the median DOR was not reached at a median follow-up of
8.1 months .
[106]

CONCLUSION: THE FUTURE OF FOLLICULAR LYMPHOMA
FL is the most common indolent lymphoma in Western countries; thus, it represents a field where the still
present unmet medical needs must be solved as soon as possible. As expressed above, the biggest failure to
date is the absence of methods able to easily depict the biological and clinical heterogeneity of a disease that
encloses many different conditions under a unique name. Consequently, in clinical practice, the standard
therapeutic induction approach is composed of a chemotherapy backbone (mainly bendamustine or
CHOP) and an anti-CD20 immunotherapy drug (rituximab or obinutuzumab), while small molecules,
BsAbs, CAR T-cells, and everything we call “targeted therapies” are licensed for R/R patients or available
up-front only in the context of clinical trials.

Since the keywords of the contemporary era are “targeted therapy” and “personalized medicine”, we think
that FL represents a great model where we can strive to achieve this future direction. As stressed in the
manuscript, heterogeneity is very high among different patients, but it can also be present in the same
patient at different sites. On the other side, as the drug armamentarium is huge, the goal should be to select