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Page 16 of 25 Lue et al. J Cancer Metastasis Treat 2022;8:11 https://dx.doi.org/10.20517/2394-4722.2021.193

[149]
refractory to their last line of therapy . In patients with R/R DLBCL who were CAR T-cell naive and
treated at doses ≥ 80 mg (n = 10), the CR and ORR rate was 60% with a duration of response (DOR) of 10.3
months. Those who were refractory to prior CAR-T cell therapy and treated at ≥80 mg (n = 21), remarkably
had an ORR of 33.3%, CR rate of 23.8% and median DOR of 2.8 months. The rates of Grade 3 CRS and
neurotoxicity were 6.3% and 2.3%, with one observed Grade 4 CRS event noted. Epicoritamab, a
subcutaneous administered BsAb against CD3-CD20, with proposed improved side effect profile due to its
route of administration, has completed phase I evaluation with RP2D of 48mg based on pharmacokinetic
[150]
profiling . In DLBCL patients treated at ≥ 48 mg (n = 7), all patients achieved a response, with 2 of 7
(28.6%) attaining a CR and 5 of 7 (71.4%) achieving a PR. Four patients were treated previously with CAR-T
cell therapy, all of which achieved a response (2 CRs, 2 PRs). Lastly, glofitamab, a 2:1 BsAb that bivalently
binds to CD20 malignant B-cells and monovalent binding to CD3 on T-cells, has demonstrated superior
potency in pre-clinical models compared to 1:1 BsAbs in conjunction with pre-treatment with
[151]
obinutuzumab (used to mitigate CRS) . The phase I/Ib evaluation of glofitamab demonstrated an ORR of
50.0% in 24 evaluable aggressive NHL patients, and a CR rate of 29.2% . The most common AEs were CRS
[152]
(57.9%), none of which were Grade 3 or higher, pyrexia (31.6%), neutropenia (28.9%), thrombocytopenia
(28.9%) and hypophosphatemia (28.9%). Ultimately, the postulated enhanced tumor killing of this newer
class of 2:1 CD20-CD3 BsAb compared to traditional 1:1 binding will require further clinical trial
investigation.

Another emerging agent is the trispecific antibody CMG1A46 which engages CD19-CD20-CD3
simultaneously, targeting not only CD19+/CD20+ DLBCL, but also those patients who relapse and lose
expression of CD20 . In vivo and in vitro studies have demonstrated improved efficacy compared to 1:1
[153]
BsAbs, and a phase I clinical trial is planned for the near future.

Another unique class of therapy that leverages immunological aspects is Chimeric antigen receptor T-cell
therapy (CAR-T cell therapy). Thus far, autologous CAR-T cell constructs against CD19 (axicabtagene
ciloleucel, lisocabtagene maraleucel, tisagenlecleucel) have been FDA approved in patients with R/R DLBCL
who have failed two or more lines of therapy. Three large phase III clinical trials have attempted to move
the CAR-T cell indication to the second-line setting, particularly evaluating patients who are deemed
chemo-resistant (primary refractory or relapsed ≤ 12 months from first-line chemoimmunotherapy). Two
of the three randomized trials demonstrated clinical benefit compared to autologous stem cell transplant
(Zuma-7, TRANSFORM) [154,155] , while the third randomized trial failed to meet its primary endpoint
(BELINDA) . Several possibilities have been postulated to reconcile these differences in outcomes,
[156]
including the high proportion of patients enrolled in the BELINDA trial experiencing progression of disease
at week 6 (prior to CAR-T cell infusion) in part due to a delay in CAR-T cell manufacturing (median time
to infusion: 52 days, range 31-135 days).

Additionally, as more follow-up data has become available, it has become apparent that approximately 30-
50% of patients who initially respond to anti-CD19 CAR-T cell will suffer a relapse, with the majority
occurring within one year of infusion . The mechanisms behind some of these relapses have been
[157]
attributed to limited persistence of the cellular products and downregulation/loss of CD19, leading to
antigen escape . Given these findings, potential combinations with targeted agents in combination with
[158]
autologous anti-CD19 CAR T-cell have been studied. Qin et al. demonstrated that the combination of
[159]
ibrutinib with lisocabtagene maraleucel led to improved CAR T-cell effector function translating into
[159]
improved survival of CD19 tumor-bearing mice . Lenalidomide has demonstrated in vivo synergy with
[160]
both anti-CD19 and anti-CD20 CAR-T cell products , and more recently has been documented to induce
responses in patients relapsing post-CAR T-cell infusion likely due to both an anti-tumoral effect and