CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy

Abstract

Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…24-27 It is important to note that also CD22 specific CAR T cells have recently proven effective in BCP-ALL and may, in the future, provide another valid treatment option for infants and children. 28 …”

“…9 , 11 , 15 CD22 specific immunotherapies (e.g. the ADC inotuzumab ozogamicin 35 and CD22 CAR T cells 28 ) or antibodies against myeloid targets may represent valid treatment options in that situation. A promising future concept for the therapy with Fc engineered antibodies is the combination of two antibodies of different specificities for simultaneous targeting of two antigens, which should hamper tumor escape by loss of one of the targets.…”

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

“…The striking efficacy of this therapeutic strategy has led to the rapid approval of 2 CAR-T therapies: tisagenlecleucel and axicabtagene ciloleucel, with more approvals expected. Although the vast majority of CAR-T-cell trials for hematologic diseases have focused on CD19redirected T cells, there are a number of new trials targeting other B-cell antigens (including CD20, CD22, CD30, and B-cell maturation antigen [109][110][111][112], T-cell antigens, as well as early trials targeting antigens associated with acute myeloid leukemia. [113][114][115][116][117][118][119][120][121][122][123][124] The elements of success with CAR-T therapies As with HCT, CAR-T-cell therapies are composed of multiple stages, and at each stage, critical elements exist that contribute to success or failure.…”

“…Longer follow-up, focused on the stability of CR for years after infusion, is beginning to be reported and provides both reason for celebration and also a mandate for further optimization of these therapeutics. 138,144,152,173 Thus, recent work from multiple centers in the United States and China have documented high CR rates as well as sustained remissions in patients treated with CD19-CAR-T cells, both with and without additional consolidation, 108,111,[136][137][138][144][145][146][147][148][149][150][151][152][153][154][155]173 striking results given the high-risk patient populations that have been treated. However, it is now clear that for most patients, the CR is not followed by long-term remission, with more than half of patients ultimately relapsing following CAR-T therapy.…”

“…In B-cell ALL, these relapses are both of CD19 1 leukemia (indicating lack of long-term efficacy of the CARs) and of CD19 2 clones, indicating mutational escape as a pivotal event in disease relapse. 111,112,137,138,144,152,154,155,173,[175][176][177] The next generation of CARs is tackling both of these modes of treatment failure, and if successful, could further reduce the need for postremission therapies.…”