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Lue et al. J Cancer Metastasis Treat 2022;8:11 https://dx.doi.org/10.20517/2394-4722.2021.193 Page 15 of 25

risk of progression/relapse/death as compared to standard of care R-CHOP (HR: 0.73; 95%CI: 0.57-0.95; P =
0.02). However, there was no difference in CRs (78% vs. 74%, respectively, P = 0.16) or OS (2-year: 88.7% vs.
88.6%). Polatuzumab-vedotin is currently under investigation in combination with salvage chemotherapy
[139]
regimens such as R-GemOx and R-ICE, as well as in combination with venetoclax/rituximab , with the
latter demonstrating a relative safe toxicity profile and median PFS and OS of 4.4 months and 11.0 months,
respectively.

Tafasitamab, a humanized anti-CD19 monoclonal antibody, gained FDA approval in combination with
lenalidomide for R/R DLBCL (> 1 prior line of therapy) after the L-MIND study demonstrated an ORR and
CR rate of 54% and 32%, respectively, with a median PFS of 16.2 months . In an updated analysis, the
[140]
[141]
median DOR was reported to be 34.6 months . The FIRST-MIND study is evaluating the addition of
[142]
tafasitamab plus lenalidomide to R-CHOP in intermediate-high risk DLBCL (NCT04134936) . Similarly,
loncastuximab tesirine, an antibody-drug conjugate against CD19, received FDA approval in 2021 after
results demonstrated an ORR of 48.3%, with a CR rate of 24% (35/145) and a PR rate of 24% (35/145) in a
heavily pretreated R/R DLBCL population .
[143]
CD47 is expressed by malignant cells as a means to evade macrophages and other members of the innate
immune system . The novel anti-CD47 monoclonal antibody, magrolimab, is currently in development
[144]
for R/R DLBCL as well as acute myeloid leukemia. This monoclonal antibody effectively inhibits a “do not
eat me” signal and induces phagocytosis of lymphoma cells by inhibiting the interaction of CD47 and
SIRP . Thus far, a phase Ib study of magrolimab in conjunction with rituximab for the treatment of R/R
[145]
DLBCL or FL demonstrated an objective response and CR of 40% and 30%, respectively, for patients with
DLBCL . A notable adverse event was anemia (attributed to the elimination of aging red blood cells) and
[146]
infusion-related reactions which were circumvented by priming (1mg/kg) and subsequent maintenance
dosing of magrolimab.

Bispecific antibodies (BsAb) are recombinant bispecific proteins that have the dual binding capacity,
recognizing two different antigens, and in turn, are able to redirect T-cells to malignant cells in order to
mediate a T-cell response and T-cell directed enhanced tumor cell death. Blinatumomab, the first-in-class
CD3-CD19 BsAb, has been approved for relapsed acute lymphoblastic leukemia, with limitations of a short
half-life requiring a continuous infusion. Next generation BsAbs have shown promising efficacy in R/R
DLBCL, including relapse after CAR T-cell therapy, and are easier to administer compared to
blinatumomab. Other benefits of BsAbs are that they are ‘off-the-shelf’ products, requiring no additional
time for manufacturing, such as in the case of autologous CAR-T-cell therapies. Mosunetuzumab, a CD3-
CD20 BsAb, is currently being studied in indolent and aggressive NHL and has demonstrated a single agent
ORR of 37% (46/124) and CR of 19% (24/124) in patients with aggressive NHL . Notably, of the 30
[147]
patients who progressed after CAR T-cell therapy, 18 patients were available for response, with four patients
(23%, 4/18) achieving a CR, and a total ORR of 39% (7/18). Twenty-eight percent of patients experienced
cytokine release syndrome (CRS), with 1.4% of patients experiencing Grade 3 CRS, all of which resolved
with the administration of tocilizumab. Neurological toxicity was observed in 44% of patients, with the
majority being Grade 1 and 2 (27.4% and 12.6%, respectively). Mosunetuzumab is currently being evaluated
in a host of clinical trials for NHL, including the GO40515 study (NCT03677141), in which
mosunetuzumab is combined with CHOP or CHP-Polatuzumab in the first-line setting for DLBCL as well
as a single agent in the treatment-naive elderly/unfit patients (NCT03677154) .
[148]

Several other CD3-CD20 BsAbs have entered clinical development as well. The phase I study of
odronexatamab was conducted in a highly refractory patient population, with 80.3% determined to be