Page 6 - Read Online

Page 2 of 14 Haydu et al. J Cancer Metastasis Treat 2021;7:36 https://dx.doi.org/10.20517/2394-4722.2021.39

NHLs range from highly aggressive malignancies which are typically fatal without treatment to indolent
[2]
diseases, and thus treatment approaches vary based on histology and clinical presentation .
The most common NHL is diffuse large B-cell lymphoma (DLBCL), an aggressive lymphoma that can be
cured with standard frontline chemoimmunotherapy in 60%-70% of patients but with historically poor
outcomes for relapsed/refractory disease. Patients with relapsed DLBCL after autologous stem cell
transplant (ASCT) or with chemotherapy-refractory disease have a particularly dismal prognosis, with a
median overall survival (OS) of only 6 months . Mantle cell lymphoma (MCL) represents approximately
[3]
6% of all newly diagnosed NHLs in the United States and is typically responsive to frontline
chemoimmunotherapy but invariably recurs and has a median OS of approximately 10 years. Outcomes are
worse for MCL patients with disease progression after Bruton’s tyrosine kinase inhibition (BTKi), with a
[4-6]
median survival of only 3-11 months in this setting . Follicular lymphoma (FL) and marginal zone
lymphoma (MZL) are characteristically indolent B-cell lymphomas that are highly responsive to upfront
chemoimmunotherapy strategies and may not limit life expectancy, but none the less remain incurable in
the majority of cases. FL and MZL patients who relapse within 2 years of initial therapy have a much worse
[7]
prognosis, with a median OS of only 5 years . Chronic lymphocytic leukemia (CLL)/small lymphocytic
leukemia (SLL) is an indolent B-cell lymphoma which is highly treatable with targeted agents yet remains
incurable, and tumors with certain high-risk molecular features, including 17p deletion or TP53 mutations,
[8]
which progress after BTKi and/or BCL2-directed approaches confer an inferior prognosis . Thus, there is a
critical need for additional treatment options for patients across the spectrum of B-cell lymphomas, and
chimeric antigen receptor (CAR) T-cell therapy is poised to help fill this need.

Biology of CAR T-cells
Currently available CAR T-cells are generated by transducing a patient’s autologous T-cells with inactivated
viral vectors (lentiviral or retroviral constructs) to produce T-cells capable of expressing an antigen receptor
targeted to a tumor cell surface antigen, along with a transmembrane spacer, a co-stimulatory domain
(usually CD28 or 4-1BB), and an intracellular signaling domain (CD3z) to lead to T-cell activation. CAR T
approaches allow for MHC-independent recognition of tumor cells, thereby conferring the specificity of a
monoclonal antibody to a T-cell. The most widely studied CAR T products now FDA-approved in
[12]
[13]
aggressive large B-cell lymphomas [9-11] , MCL , and FL target the CD19 antigen, which is broadly
expressed on mature B-cell lymphomas as well as on B-cell acute lymphoblastic leukemia. Full activation of
[14]
a T-cell requires both a primary signal through the TCR as well as co-stimulation to avoid anergy , and
incorporation of co-stimulatory domains, which were absent in first generation CARs, has led to
improvements in clinical efficacy . The type of co-stimulatory domain leads to differences in CAR T-cell
[15]
dynamics, with CD28 co-stimulation resulting in quicker and higher peak CAR T expansion compared to 4-
1BB-co-stimulation , and is associated with differences in toxicity profiles (see below).
[16]

After a patient’s T-cells are collected via apheresis, the manufacturing process typically takes 3-4 weeks.
Patients may or may not receive “bridging” chemotherapy to control their underlying malignancy while
awaiting receipt of their genetically modified CAR T-cells. Prior to CAR T-cell infusion, patients receive
lymphodepleting chemotherapy which has been shown to promote proliferation and expansion of the T-cell
product and to prevent an immune response directed against the CAR T-cells . Patients are subsequently
[17]
monitored for potential toxicities.

APPROVED CAR T-CELL PRODUCTS
DLBCL and other large B-cell lymphomas
There are now three FDA-approved anti-CD19 CAR T-cell products for relapsed/refractory DLBCL and