High CD33 expression in acute myeloid leukemia (AML) with mutated <i>NPM1</i> provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity.
We performed a preclinical validation using a model of CD33<sup>+</sup> AML, and generated iC9 CAR T-cells co-expressing a CAR targeting the AML-associated antigen CD33 and a selectable marker (ΔCD19).ΔCD19 selected (sel.) iC9-CAR.CD33 T-cells were effective in controlling leukemia growth in vitro, and could be partially eliminated (76%) using a chemical inducer of dimerization that activates iC9.
We tested whether a single nucleotide polymorphism (SNP) that affects splicing of CD33 predicted response to treatment in adults with acute myeloid leukemia (AML) who received the novel CD33 antibody-drug conjugate SGN-CD33A.
Therefore including a megakaryocytic marker in the primary flow cytometry panel is important so that these cases are not under-diagnosed as Acute myeloid leukemia because of expression of CD13 and CD33 only.
We evaluated gemtuzumab ozogamicin (CD33-targeted drug) used on a compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia Berlin-Frankfurt-Münster studies, and identified 76 patients (<18 years) with highly-advanced and pre-treated AML [refractory <i>de novo</i> acute myeloid leukemia (n=10), <i>de novo</i> AML refractory to relapse (1<sup>st</sup> early: n=41; 1<sup>st</sup> late: n=10; 2<sup>nd</sup> or more: n=10), and secondary AML (n=5)].
Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody-drug conjugate to be approved for CD33-positive acute myeloid leukemia (AML).
The most common (>30%) side effects of Mylotarg when used together with daunorubicin and cytarabine are hemorrhage and infection.The full indication is as follows: "Mylotarg is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL).
However, outside of HSCT, only the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin is currently approved as an antibody-targeted therapy for AML.
The therapeutic landscape is rapidly changing, with eight new drugs approved by the Food and Drug Administration within the last 2 years, including midostaurin and gilteritinib for FLT3 mutant newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML), respectively; CPX-351 (liposomal cytarabine and daunorubicin) for therapy-related AML and AML with myelodysplasia-related changes; gemtuzumab ozogamicin (anti-CD33 monoclonal antibody conjugated with calicheamicin) for newly diagnosed and R/R CD33-positive AML; enasidenib and ivosidenib for IDH2 and IDH1 mutant R/R AML, respectively.
We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33-targeted ADCs.
Bone marrow flowcytometric analysis showed myeloblast count of 74%, which expressed CD13, CD33, CD117 and HLA-DR. A diagnosis of AML (M2 type) was made and vulvar MS was the earliest symptom.
Moreover, the optimized aptamer S30-T1 (i.e., core region of S30) was conjugated with doxorubicin (Dox) to synthesize S30-T1-Dox conjugates, which could specifically inhibit CD33 positive acute myeloid leukemia HL-60 cell proliferation by arresting the cell cycle at the G2 phase.
To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients.
CD33 is detected on the surface of myeloid blasts in many patients with acute myelogenous leukemia and is the target of the antibody drug conjugate gemtuzumab ozogamicin (GO).
While several candidate therapeutics have failed at various stages of clinical testing, improved survival of some patients receiving the CD33 antibody-drug conjugate gemtuzumab ozogamicin has provided first evidence that monoclonal antibodies have a role in the armamentarium against AML.
Using a human AML cell line (HL-60), we modeled a postremission marrow with minimal residual disease and showed that the transplantation of CD33-ablated HSPCs with CD33-targeted immunotherapy leads to leukemia clearance, without myelosuppression, as demonstrated by the engraftment and recovery of multilineage descendants of CD33-ablated HSPCs.
This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery.
In summary, the final results of this trial confirm that FLAI-GO is an active and safe treatment strategy for CD33-positive AML patients aged ≤ 65 years, allowing a high ORR, a good disease debulking, favorable safety profile, low DDI, and subsequent high SCT rate.
Approaches to harness the body's own T cells against AML include antibodies that recruit and induce cytotoxicity of tumor cells by T cells (bispecific T-cell engager [BiTE] such as CD33 x CD3 (e.g.AMG 330) or CD123 x CD3 (e.g. flotetuzumab, JNJ-63709178) or antibodies that block immune checkpoint receptors CTLA4 (e.g. ipilimumab) or PD1/PD-L1 (e.g. nivolumab, pembrolizumab, avelumab) on T cells, unleashing the patients' T cells against leukemic cells.
Using a CD33-specific CAR in an acute myeloid leukemia (AML) model, we show how CAR expression alters T cell differentiation in a ligand independent manner.