Advances and Limitations in CD20-Targeted CAR T-Cell Therapy

The advent of chimeric antigen receptor (CAR) T-cell therapy significantly impacted the treatment landscape for certain hematologic cancers, with 4 CD19-targeted agents gaining FDA approval for several malignancies. Now, CD20 CAR T-cell therapy represents another potentially effective treatment option for patients with relapsed or refractory non-Hodgkin lymphoma (NHL), as detailed in a recent review published in ImmunoMedicine.

CAR T-cell therapy involves genetically engineering a patient’s own CAR T cells to target receptor proteins on tumor cells before reinfusing them, and it has curative potential in hematologic cancers. There are 4 currently approved CD19-targeted CAR T-cell therapies and 2 FDA-approved B-cell maturation (BCMA)–directed CAR T-cell therapies.

CD20 and other target antigens are currently being studied, and CD20 represents a potentially effective target—particularly in patients with NHL. NHL is a common type of B-cell malignancy and typically carries a poor prognosis, but CD20 CAR T-cell therapy has been effective in patients with relapsed or refractory NHL. 

“CD20 is a tetra-transmembrane protein that primarily expresses on mature B-cells and malignant B-cells but not in early B-cell progenitors or later mature plasma cells,” the authors wrote. “CD20 plays a vital role in developing B-cells’ differentiation and development into plasma cells, which actively participate in B-cell activation and proliferation. It presents in more than 90% of B-cell lymphomas, making it a perfect target molecule for NHL.”

One advantage of targeting CD20 is its prominence in B-cell lymphomas. While the exact role of CD20 antigens is not entirely clear, it is known to help exhaust the B-cell compartment and therefore plays an important part in B-cell lymphoma treatment. In a phase 2a trial of 11 patients with refractory or relapsed CD20-positive B-cell lymphoma, the overall response rate (ORR) was 81.8% and 6 patients experienced complete remission (CR) while 3 experienced partial remission (PR). One patient experienced CR for 27 months, and the median progression-free survival (PFS) was more than 6 months.

In studies where CD20-targeted CAR T cells were shown effective in patients with B-cell lymphomas, they were also shown to activate and recognize malignant cells even when antigen expression was low. This suggests CD20 CAR T-cell therapy may be an effective option for patients with CD20 downregulated lymphoma or individuals who are refractory to CD20 monoclonal antibody (mAb) therapy.

CD20 CAR T-cell therapy also comes with limitations, including the fact that patients treated with CAR T-cell therapy in general are typically individuals who have relapsed or are refractory to prior lines of therapy. Certain therapies, namely the anti-CD20 mAb rituximab, could potentially exhaust normal CD20-positive B cells or cause CD20-negative tumor cell production, and loss of CD20 antigens may make patients resistant to CD20 CAR T cells. CD20 antigens are also mostly expressed on mature and malignant B cells, not on early B-cell progenitors or mature plasma cells. Still, given the high CD20 expression typically seen in NHL patients, targeting them with engineered CAR T cells is a promising approach.

Multitargeted CAR T-cell therapies are a potential solution to target relevant antigens more comprehensively. A CD19-CD20 CAR T-cell therapy has shown impressive preclinical outcomes and no severe toxicity. The dual-target therapy improved antitumor activity, but further studies on the safety of dual-target CAR T-cell therapy are needed. Another area of expansion could be allogeneic, or off-the-shelf, CAR-T cells for patients who do not have sufficient autologous cells to engineer.

Another consideration with CAR T-cell therapy overall is the risk of serious adverse events, namely cytokine release syndrome (CRS), which is the most common side effect of CAR T-cell therapy. CRS is a massive release of lymphocytes, macrophages, or myeloid cells that occurs due to the immune activation caused by treatment. Hypotension, renal failure, shock, and sometimes death can result from CRS, which generally happens days after infusion and lasts 7 to 10 days. Prescribing tocilizumab, corticosteroid, and/or etanercept can help resolve most CRS symptoms. CAR T-cell–related encephalopathy syndrome (CRES) and immune effector cell–associated neurotoxicity syndrome (ICANS) are also potential adverse effects of CAR T-cell therapy.

Overall, the review concludes that CD20 CAR T-cell therapy is an option worth exploring, despite potential safety concerns that warrant more extensive research.

“Understanding the complex resistance mechanisms in blood cancer and exploring the tumor environment in solid tumors are now significant tasks to broaden the application of CD20 CAR T-cell therapy,” the authors wrote. “In short, CD20 CAR T-cell therapy's future is promising to improve patients’ quality of life.”

Reference

Tan Su Yin E, Xian Hu Y, Huang H. The breakthrough and the future: CD20 chimeric antigen receptor T-cell therapy for hematologic malignancies. Immunomedicine. Published online October 5, 2022. doi:10.1002/imed.1039