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[161]
immunomodulatory mechanisms . Another way to leverage the immune axis is the addition of PD-
1/PDL-1 inhibitors to CAR-T cell products as the expression of PD-1 is enhanced after receipt of anti-CD19
CAR-T cell infusion [162,163] . As proof-of-principle, a case report of a patient with refractory DLBCL who
progressed rapidly on ZUMA-1, was administered nivolumab 3 mg/kg (11 days after infusion with
axicabtagene ciloleucel), leading to a rapid re-expansion of CAR T-cell product within 48 hours of receipt of
[164]
nivolumab and eventual reduction of tumor volume after completing two additional nivolumab doses .
This, along with pre-clinical data, has laid the foundation for ZUMA-6, which is evaluating axicabtagene
[165]
ciloleucel in combination with atezolizumab (anti-PD-L1 antibody) in patients with refractory DLBCL .
There is also emerging dating supporting the use of PI3K inhibitors during CAR T-cell production as it can
[166]
enhance the expansion of CD8+ CAR T-cells, with durable persistence and increased efficacy . In addition
to combination therapies, novel CAR-T cell products have been explored in order to overcome the
resistance associated with anti-CD19 CAR T-cell therapy, including novel autologous CAR-T cell products
against CD20 and CD22 , tandem CAR-T cell therapies in which CD19/CD20 are engaged
[167]
[168]
simultaneously [169,170] , and the development of allogenic CAR-T cell therapy, with the latter obviating the
need for leukapheresis.

Although not immunologically-based, selinexor, an oral inhibitor of XPO1-mediated nuclear transport, has
also recently been FDA approved, and its therapeutic index is observed across subtypes. Selinexor
demonstrated an ORR of 28% (36/127) with 12% achieving a CR (15/127) in the R/R DLBCL population,
and a DOR of 9.3 months (95%CI: 4.8-23.0) . The most common grade 3-4 AEs were thrombocytopenia (
[171]
n = 58), neutropenia (n = 31), anemia (n = 28), fatigue (n = 14), hyponatremia (n = 10), and nausea (n = 8).
Subgroup analysis demonstrated that responses were similar irrespective of COO, age, gender, previous
therapy, refractory status and history of ASCT.

FUTURE DIRECTIONS: WHAT THE FUTURE OF DIFFUSE LARGE B-CELL LYMPHOMA
CARE MAY LOOK LIKE
Despite our deeper understanding of the complex molecular landscape of DLBCL as well as several attempts
to leverage this understanding in a logical matter, we have only recently improved upon our standard of
care frontline chemoimmunotherapy. Although R-CHOP has remained a cornerstone in therapy for two
decades, several improvements in the R/R setting have been observed, ranging from targeted oral molecular
agents to antibody-drug conjugates to cellular therapy. In the past five years, the only drugs/therapies that
have successfully achieved FDA approval for DLBCL (CD19 CAR T-cell therapy, polatuzumab vedotin,
tafasitamab, loncastuximab, selinexor) are not used in a subtype-specific matter. In fact, these newer
molecular DLBCL classifications are not readily available in the community and will require the
development of rapid, reproducible assays in order to be widely adapted. A focus on the integration of
immunologic and small molecule agents that are universal to all DLBCL subtypes into our treatment
paradigms avoids the need to develop highly specific and costly molecular assays to identify a target
population. Along those lines, until rapid and reliable assays are developed, one rational way to improve the
R-CHOP backbone is the addition of agnostic agents such as monoclonal antibodies that avoid the need for
detailed molecular subtyping that often leads to a longer diagnosis-to-treatment time, while reserving a
more precision based approach in the R/R setting. Once the development of a reliable assay is created based
on companion studies in the R/R clinical trial setting, the assay can be applied in the frontline setting, where
we have come to acknowledge the importance of the diagnosis-to-treatment interval . Alternatively, in
[25]
order to avoid delay in the initiation of treatment and permit deep molecular analysis, another option is to
incorporate pre-phase therapy as performed by Pfreundschuh and colleagues in the upfront or even R/R
[172]
clinical trial setting. There is also a dire need to develop broader eligibility criteria to evaluate novel
precision medicine-based agents and their associated companion diagnostics as it is clear that high-risk