TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML

Abstract

Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

“…Moreover, flotetuzumab induced CR in almost half of TP53 mutated patients enrolled. Patients with TP53 abnormalities who achieved a complete response experienced encouraging OS (median 10.3 months; range, 3.3–21.3 months) ( 81 ).…”

Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia

“…In accordance to the presented data here, other studies showed that patients with mutations in TP53 and genes involved in the signal transduction presented slightly increased numbers of T cells within the BM. which has in some cases a prognostic value in patients with proved TP53 mutations [ 54 , 55 ]. In addition, another study presented data demonstrating that patients with TP53 mutations exhibited a reduced number of helper T cells, but a significant increase in Treg and MDSC.…”

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…In R/R AML patients with TP53 mutations, 47% (n=7/15) demonstrated CR to flotetuzumab and displayed increased tumor inflammation signature as well as CD8, inflammatory chemokine, and PD-1 expression compared with non-responders. These patients who achieved CR experienced prolonged survival ( 138 ). Phase I/II trial is being evaluated in R/R AML and high-risk MDS patients (NCT02152956) to further assess the efficacy of flotetuzumab therapy; (ii) XmAb14045 (SQZ622) is another CD123 x CD3 bsAb.…”