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Haydu et al. J Cancer Metastasis Treat 2021;7:36 https://dx.doi.org/10.20517/2394-4722.2021.39 Page 11 of 14

Advances in CAR T design and production
As highlighted previously, a proportion of patients who undergo apheresis never make it to CAR T infusion,
which in addition to progressive disease despite bridging therapy can also be due to CAR T production time
and/or manufacturing failures. Clinical trials are ongoing with allogeneic CAR T-cells, which by virtue of
being “off the shelf”, minimize wait time and may even abrogate the need for bridging and its associated
pitfalls. Moreover, allogeneic CAR T approaches circumvent the risk of dysfunctional autologous T-cells
arising from exposure to multiple prior therapies and/or primary disease-associated impaired T-cell
[60]
function . ALPHA-2 is an ongoing single arm open label phase 1/2 clinical trial evaluating the safety and
efficacy of an allogeneic anti-CD19 CAR T-cell product (ALLO-501A) in relapsed/refractory large B-cell
lymphoma (NCT04416984). While allogeneic CARs come with the theoretical risks of rejection and graft
versus host disease (GVHD) that are absent with autologous products, gene editing approaches with
[61]
CRISPR-Cas9, TALEN , or ZFN technologies can be used to disrupt HLA and native T-cell receptor gene
expression to reduce the risks of rejection and GVHD, respectively. Studies are also ongoing with allogeneic
CAR-transduced products generated from NK cells, which have been associated with a lower risk of CRS,
neurologic toxicity, and GVHD compared to T-cell derived products. In early results from a phase 1/2
clinical trial (NCT03056339) of HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood
administered to 11 patients with relapsed or refractory CD19-positive NHL or CLL, 73% (8/11) of patients
had a response and 7/8 responses were complete, with no instances of CRS, neurologic events, or GVHD .
[62]

While approximately half of CAR T-treated patients have long term responses, about half of patients do not
respond or relapse, underscoring the need for novel CAR T approaches addressing mechanisms of
resistance, including target antigen loss, immune escape or silencing, T-cell exhaustion, and loss of
persistence. Investigations into antigen escape from lost CD19 expression on lymphoma cells include
targeting multiple antigens at once with approaches such as tandem CARs which co-express two targets
(e.g., CD19 and CD22) or pools of cells transduced with CARs conferring different antigen specificity.
[63]
Combinations of CAR T-cells with immune checkpoint blockade and/or immunomodulatory agents as
discussed previously may help address immune escape. Moreover, CAR T-cells have been engineered to
secrete cytokines such as IL-12 and IL-18 to overcome the immune suppressant tumor
[66]
microenvironment [64,65] or to directly inhibit immune checkpoints . Other novel approaches include third
generation CARs which incorporate a co-stimulation domain to enhance T-cell activation or insertion of
[67]
the CAR gene at the TRAC locus to optimize activation and reduce T-cell exhaustion .
[68]
CONCLUSION
CAR T-cells have ushered in a new era of therapeutic options for patients with relapsed/refractory large B-
cell, mantle cell, and FLs. Ongoing studies in expanded histologies including relapsed/refractory indolent B-
cell lymphomas, and studies addressing optimal CAR T-cell timing and administration in large B-cell
lymphomas, may ultimately lead to additional approvals. While significant advances continue to be made in
the CAR T-cell space, ongoing research particularly into the biology of CAR T resistance may lead to novel
approaches that translate into improved outcomes for lymphoma patients.

DECLARATIONS
Authors’ contributions
Researched, wrote, edited and reviewed the manuscript: Haydu JE
Wrote, edited and reviewed the manuscript: Abramson JS

Availability of data and materials
Not applicable.