Although CD19 has proved to be an attractive and effective target for chimeric antigen receptor (CAR) T-cell therapies in hematologic malignancies, a significant subset of patients treated with this groundbreaking form of immunotherapy eventually relapse, with some developing a more aggressive and harder-to-treat form of their disease.1-3
CAR therapies are composed of genetically engineered T cells designed to target tumor-associated antigens (TAAs). The 2 CAR T-cell therapies that the FDA has approved thus far, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta), target the CD19 protein, which is highly expressed in a variety of B-cell malignancies.
As investigators seek to understand the mechanisms of resistance that develop with these and other CD19-directed anticancer therapies, some are turning their attention to alternative targets that could offer a way to stay 1 step ahead of evolving cancers. In this respect, CD22 shows particular promise.
CAR T-cell therapies that target CD22 are beginning to demonstrate potential value, particularly in patients who have relapsed following treatment with CD19 CARs. Additionally, CD22 is becoming an important target in its own right in hematologic malignancies. Two novel therapies directed against CD22, inotuzumab ozogamicin (Besponsa) and moxetumomab pasudotox-tdfk (Lumoxiti), have gained FDA approvals during the past year.
CD22 is a glycoprotein and a member of the immunoglobulin G gene superfamily. It is expressed across all stages of B-cell differentiation but absent from mature plasma cells. Like CD19, CD22 expression is restricted to B cells and helps regulate the immune response through B-cell receptor signaling (FIGURE).4
Additionally, CD22 is highly expressed in B-cell malignancies. Importantly, CD22 expression is usually retained in tumors that have lost CD19 expression. In the earlier stages of B-cell development, CD22 is found inside the cell, though later on it is expressed on the membrane. It plays a number of different roles. Significantly, it has an inhibitory function in B-cell signaling, establishing a base-line level of antigen binding that must be exceeded prior to B-cell activation, to help keep humoral immunity in check.5,6
CAR T-cell therapies directed at CD22 are being studied in a growing number of clinicaltrials throughout the world and in preclinical programs. In the United States, academic centers are leading several phase I trials testing novel approaches, including CAR combinations (TABLE)
. Meanwhile, at least 2 dozen other trials are ongoing in China and Europe, according to clinicaltrials.gov.
CD19 Targeting Makes Impact
CAR T cells are a form of adoptive cell therapy in which the effector cells of the immune system are transplanted into a patient to boost the antitumor immune response. The T cells are genetically engineered outside the body to express a CAR that is designed to target a TAA. CARs are artificial T-cell receptors (TCRs) made of the single-chain variable fragment from an anti- body, which confers antigen specificity, fused to an intracellular portion composed of the CD3ζ chain of the TCR and 1 or more costimulatory domains, which trigger T-cell activation. In this way, an antibody-like sensitivity is essentially grafted onto a T cell.7,8
Figure. CAR T Cells in Signaling Network4
BCR indicates B-cell receptor; CAR, chimeric antigen receptor; CCR4, CC chemokine receptor 4. CAR-modified T cells targeting CD19 and CD22 transmembrane proteins on a malignant B cell. T-cell activation leads to apoptosis of the cancer cell.
Last year marked the first FDA approvals of this type of immunotherapy. These approvals and much of the research conducted to date have focused on targeting the TAA CD19—an ideal target for the treatment of leukemia and lymphoma thanks to its restriction to B cells and its frequent expression in B-cell malignancies.
Tisagenlecleucel gained the FDA’s approval in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. The decision was based on findings from the single-arm, phase II ELIANA trial, in which the overall response rate (ORR) was 81%, including complete remission (CR) in 60% of patients.9
The drug subsequently was approved for treating adults with relapsed or refractory (r/r) B-cell lymphoma after 2 or more lines of systemic therapy.
In October 2017, axi-cel was approved for treating patients with r/r large B-cell lymphoma after 2 or more lines of systemic therapy. The phase II ZUMA-1 trial demonstrated an ORR of 82%, with CR in 54% of patients 23 years and older (median age, 58 years; range, 23-76) with refractory large B-cell lymphomas.10