CD22 expression

The findings prompt reflection also on the broader role of epigenetics in decoupling of replication from lineage differentiation activation by the B cell lineage master transcription factor hub. Such oncogenesis and resistance mechanisms, being predictable and epigenetic, offer practical opportunities for intervention, potentially non-cross-resistant and safe vis-à-vis present cytotoxic and CAR-T treatments.

Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

m971-CD28-CD3ζ NK-92 cells efficiently lysed CD22-expressing lymphoma cell lines and produced large amounts of cytokines such as IFN-γ and GM-CSF but a lower level of IL-6 after coculturing with target cells. Based on our results, it is evident that transferring m971-CD28-CD3ζ NK-92 cells could be a promising immunotherapy for B cell lymphoma.

P2, N=80, Recruiting, Children's Oncology Group | Active, not recruiting --> Recruiting

P3, N=1895, Active, not recruiting, National Cancer Institute (NCI)

Our findings highlight the importance of defining the basis of CD22 escape, and eradication of residual disease prior to HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss, and provide opportunities to improve therapeutic approaches and overcome resistance.

Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

P1, N=52, Active, not recruiting, Stanford University | Trial completion date: Dec 2024 --> Dec 2037

P1, N=56, Active, not recruiting, Crystal Mackall, MD | Recruiting --> Active, not recruiting

CD19low resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both BTK and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.

P2, N=64, Recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P1, N=10, Active, not recruiting, Stanford University | Suspended --> Active, not recruiting | N=52 --> 10 | Trial completion date: Aug 2035 --> Sep 2036 | Trial primary completion date: Aug 2025 --> Oct 2023

P3, N=700, Completed, Charite University, Berlin, Germany | Active, not recruiting --> Completed

Combining ADCT-602 + pacritinib was beneficial in ADCT-602-resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematological cancers.

P1, N=123, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

Fourteen patients underwent both CD19 and CD22 CAR-T-cell therapy, four underwent CD19 CAR-T-cell therapy, and three underwent blinatumomab therapy. Grade 1-3 hepatotoxicity occurred in five patients (23.8% ), one child with no response experienced hepatic veno-occlusive disease (HVOD) during salvage transplantation and recovered completely. For patients with heavily treated R/R B-ALL, including those who had undergone allo-HSCT and CD19/CD22 CAR-T-cell therapy, the two-dose regimen of inotuzumab resulted in a CR rate of 66.7%, and the frequency of hepatotoxicity and HVOD was low.

P1, N=52, Active, not recruiting, Stanford University | Recruiting --> Active, not recruiting | N=92 --> 52 | Trial completion date: Sep 2034 --> Dec 2024 | Trial primary completion date: Apr 2023 --> Dec 2024

P1, N=52, Suspended, Stanford University

P2, N=32, Recruiting, St. Jude Children's Research Hospital

P1/2, N=93, Recruiting, Stephan Grupp MD PhD | Trial completion date: Jan 2026 --> Jan 2029 | Trial primary completion date: Jan 2025 --> Jan 2027

Our data suggest that the safety and efficacy of CAR -T-cell therapy in > 70-year-old patients is not significantly different from that in 65-70-year-olds. Elderly patients with ADL scores below 95 have poor survival after CAR -T therapy, especially those over 70 years of age. However, studies on curative approaches and long-term follow-up are needed.

All patients received fludarabine (FLU) and cyclophosphamide (CTX) conditioning chemotherapy (FLU 30mg/m 2, d1-3; CTX 500mg/m 2, d1-3) before CAR-T infusions. In summary, CD19/CD22 exhibited a manageable safety but limited antileukemia activity. Our study showed that mixture of CD19 CAR-T and CD22 CAR-T cells infusion is fail to expected to compensate for the treatment of relapsed in r/r ALL and prolonging the leukemia-free survival of patients. The low-efficacy of dual-targeted CAR-T cells may be caused by the CAR19 and CAR22 cells interfere with each other and weaken the CAR-T amplification in vivo.

This would be because the PARP inhibitors were still effective in inhibiting the DNA repair in Reh-IO-R cells where the DNA repair function was not augmented. [Conclusion]The combination of IO with PARP inhibitors synergized the antileukemic effect of IO by inhibiting DNA strand break repair in CD22-positive ALL cell lines and IO-resistant ALL cells, suggesting that these results may contribute to overcoming the IO resistance mechanisms.

Recently, such pts have new hope with the wide application of a novel third-generation TKI Olverembatinib developed in China and Blinatumomab（CD19 antibody,BITE）and INOTUZUMAB OZOGAMICIN(CD22 antibody,Ino. For heavily treated RR ABL1+B ALL pts,including those after treatment with ponatinib and other TKICART and HSCT, Olverembatinib combined with monoclonal antibodies is effective and safe. In my cases, it is particularly noteworthy that one pts ,Ph like ALL with ABL1 FG, received Olverembatinib combination BITE and achieved a surprising response, so Olverembatinib may also be effective and safe for such pts. In addition, venetoclax may be used as a sensitizer for TKI or other antitumor drugs.

Integrating these two omics levels offers a better understanding of the shared and distinct molecular pathophysiology of PD and MDD in both the periphery and the brain. These findings could lead to potential diagnostic biomarkers, improving accuracy and guiding pharmacological treatments.

P1, N=123, Suspended, National Cancer Institute (NCI) | N=208 --> 123 | Recruiting --> Suspended

CD22 is a potential tumor surface antigen capable of being targeted by CAR-NK cells in ESCC. And potential therapeutics for ESCC may be developed based on immune cells expressing anti-CD22 CAR. The study also indicates that CD22 CAR-NK cells could be used in other cancers and more in vivo experiments are needed.

The fludarabine, cyclophosphamide, and alemtuzumab (FCA) LD regimen was also shown to extend host lymphocyte suppression and improve UCART22 expansion versus fludarabine and cyclophosphamide (FC) alone (Boissel N, et al...Cytokine release syndrome (CRS) occurred in 2/3 (67%) pts, with one G1 that resolved without treatment and one G2 that resolved after tocilizumab x1...Pt 3 was refractory to treatment, however this pt received bridging therapy with dasatinib for his ABL2 fusion, and on Day -1, only 47% of the leukemic cells expressed CD22 (down from 88% at screening)... As of 01 July 2023, 3 pts were enrolled into the first UCART22 P2 cohort at DL2. Pt 1 is a 17yo female with B-ALL with a hypodiploid karyotype and a germline TP53 mutation whose disease had previously failed to respond to multiagent chemotherapy, blinatumomab (blina), inotuzumab (ino), venetoclax (ven), allogeneic hematopoietic stem cell transplantation (HSCT), and autologous CD19 CAR T-cell therapy (CAR19) x2. Pt 2 is a 68yo female with Ph-negative B-ALL who relapsed with CD19-low disease after multiagent chemotherapy, ino, and blina.

Our findings demonstrated that ZNF384 rearrangement might induce antigen editing during treatment-related selective pressures in adult B cell acute lymphoid leukemia, especially in CAR-T therapy. More efforts are needed to reveal mechanisms behind it to help reduce antigen loss and relapse rate after CAR-T therapy.

Together, these results highlight the opportunity for TCR-T cells to mediate anti-leukemia responses with a potentially safer toxicity profile compared to CAR-T cells. Our work provides the basis for incorporating TCR-based immunotherapy into the treatment paradigm for patients with relapsed/refractory B-cell malignancies, improving the safety of adoptive cell therapy.

Eligibility: ≥18 years (yrs); ALL (≥5% blasts) or LBL (marrow involvement not required); CD22 expression on ≥20% of blasts; R/R to one or more cycles of CC or in the case of Philadelphia-chromosome (Ph)-positive ALL, failed by two or more TKIs, or refractory to/ineligible for ponatinib; ≥60 days from bone marrow transplant (BMT), and off immune suppression ≥2 weeks; adequate liver and kidney function; no history of liver disease including SOS; blast count ≤25 K/mL prior to treatment; no symptomatic central nervous system (CNS) disease...Two pts bridged to consolidation (donor lymphocyte infusion after 3 cycles, blinatumomab after 5 cycles) while 1 pt with KMT2A-r ALL experienced early relapse with lineage switch during second cycle...There were no delays in count recovery during C1, with median time from C1 to C2 being 30 days (range 27-42). Conclusion VEN 400mg x 21 days in combination with INO at standard doses was well tolerated and declared the recommended phase 2 dose (RP2D) with a CR rate of 100%.

In order to improve outcomes in patients with relapsed CD22 (+) NHL, or chronic lymphocytic leukemia (CLL) who failed targeted therapies and were candidates for allo-SCT, we prospectively studied the addition of InO to our standard chemo-conditioning of BFR (bendamustine, fludarabine and rituximab-Khouri Blood 2014)...Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis...Patients with CLL/MCL were previously treated with ibritunib (n=10), venetoclax (n=5), idelalisib (n=2), nivolumab (n=1) and CAR T (n=1)... Our results show that InO is safe when combined with an allo-SCT conditioning regimen and may improve survival outcomes in patients with CD22 (+) NHL. This needs to be validated in a larger number of patients. An ongoing trial at our center involves fractionating InO dose pre-and post-allo-SCT in patients with lymphoma or acute lymphoblastic leukemia receiving a reduced-intensity conditioning, and adding post-transplant cyclophosphamide to decrease the risk of GVHD.

P1/2, N=116, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P3, N=847, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2023 --> Sep 2024

P1/2, N=116, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P2, N=80, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P1/2, N=65, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P1/2, N=42, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

In this review, we explore the molecular and physiological characteristics of CD22, development of CD22 ADCs and CAR-T cells, and the available clinical data on CD22 ADCs and CAR-T cell therapies. Furthermore, we propose some perspectives for overcoming tumor escape and enhancing the efficacy of CD22-targeted therapies.

The diagnosis of HCL requires a multipronged approach. The use of clinical features, morphology, and immunophenotyping combined with ancillary techniques provides higher diagnostic accuracy and enables its distinction from other B-cell lymphoproliferative disorders (BCLPDs), leading to better patient management and treatment.

P1/2, N=40, Recruiting, Cellectis S.A. | Trial primary completion date: Jul 2023 --> Dec 2023