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May 12, 2020 04:30pm
By Lisa Astor
“Immune transcriptomic analyses of in silico and wet-lab cohorts of TP53-mutated AML suggest the presence of high T-cell infiltration and high expression of immune checkpoints and interferon-gamma signaling molecules compared with AML subgroups with other risk-defining molecular lesions."
An analysis of cases of TP53-altered acute myeloid leukemia (AML) presented at the 2020 American Association for Cancer Research Virtual Annual Meeting suggested the presence of a subgroup marked by high immune infiltration that could benefit from treatment with immunotherapy.
“Immune transcriptomic analyses of in silico and wet-lab cohorts of TP53-mutated AML suggest the presence of high T-cell infiltration and high expression of immune checkpoints and interferon-gamma signaling molecules compared with AML subgroups with other risk-defining molecular lesions,” said Sergio Rutella, MD, PhD, FRCPath, during the virtual presentation of the analysis. Rutella is a professor of cancer immunotherapy at the John van Geest Cancer Research Center at Nottingham Trent University in the United Kingdom.
The genetic drivers of immune infiltration in AML are currently unknown. The impact of TP53 mutations or inactivation on immune regulation have been largely overlooked in AML, Rutella noted, but these mutations occur in about 8% to 10% of de novo AML and can be associated with resistance to chemotherapy.
Investigators sought to assess whether TP53 abnormalities were correlated with the composition and functional orientation of the tumor immunological microenvironment in cases of AML. The study further intended to determine if these alterations could identify patients with AML that would benefit from treatment with flotetuzumab, an investigational, bispecific DART molecule that recognizes both CD123 and CD3 and facilitates redirecting host T cells to AML.
First, the investigators analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) of 147 cases of non-promyelocytic AML, including 14 cases with TP53 mutations, for immune cell type–specific and biologic activity gene signatures. These signatures were correlated with prognostic molecular markers and clinical outcomes.
Bone marrow samples were also analyzed from 42 patients with TP53-mutated AML and 22 patients with TP53 wild-type disease, all who were treatment naïve. RNA was extracted and analyzed with the PanCancer IO 360 gene expression panel.
In the AML samples from TCGA, 2 subtypes of AML emerged, an immune-infiltrated and an immune-depleted group. The immune-infiltrated group included the 14 cases of TP53-mutant AML.
All patients with TP53 mutations showed high levels of tumor inflammation signatures, inflammatory chemokines, interferon-gamma, and lymphoids. The expression of immune checkpoints PD-L1 and TIGIT, and molecules associated with an immune suppressed immune microenvironment, were significantly higher in patients with TP53 mutations.
The overall survival in these patients with TP53 mutations from the TCGA dataset was much shorter than in patients with other molecular markers (4.5 vs 18.5 months; HR, 3.43; 95% CI, 1.34-8.74; P <.0001).
The bone marrow samples of 42 patients with TP53-mutated AML showed that 84% of TP53 alterations were missense alterations. When analyzed by quantity of immune infiltration, 87% of patients with high immune infiltration had TP53 mutations, as did 75% with intermediate infiltration, and 8% with low infiltration. Additionally, higher levels of CD8, markers of cellular senescence, and negative immune checkpoints were observed in samples of TP53-mutant disease than wild-type disease.
The immune transcriptomic profile at the gene level was analyzed and identified 34 differentially expressed immune genes between TP53-mutant and wild-type cases. The genes were then assessed in silico for their ability to act as prognostic markers in cases of AML. In the 19 upregulated genes in cases of TP53-mutated AML, alterations were associated with worse relapse-free survival (11.4 vs 24.1 months; HR, 1.86; 95% CI, 1.12-3.1; P = .0068).
The ongoing phase I/II CP-MGD006-01 clinical trial (NCT0215956) was initiated to investigate the use of flotetuzumab in patients with relapsed/refractory AML.
A subgroup of 35 patients with AML who were treated with flotetuzumab at the recommended phase II dose were examined in the analysis, including 11 patients with TP53 mutations and/or 17p abnormalities and genomic loss of TP53 and 24 patients with TP53 wild-type disease. Their RNA was also extracted and analyzed for predictors of response.
The patients had a median age of 54 years (range, 27-74) and 54% were female. At baseline, 57.1% had refractory disease after primary induction failure and 68.6% of patients were classified as having adverse risk factors. The median number of prior lines of therapy was 3 (range, 1-9). The study assessed anti-leukemic activity as a measurement of response.
Nine patients had baseline bone marrow samples for immune gene expression profile, and 7 of these patients had intermediate to high immune infiltration. Of 11 evaluable patients with TP53 mutations and/or 17p abnormalities, the rate of anti-leukemic activity was 45.5%, including 2 complete responses. The median survival in these patients was 4.0 months.
Rutella noted that this survival compared favorably with historical estimates for survival in patients with TP53-mutated AML after primary induction failure (1.16 months).
Among patients who responded to flotetuzumab, the gene expression scores of tumor inflammation signatures, inflammatory chemokines, interferon-gamma, and regulatory T cells were all significantly higher at baseline than in non-responders. This highlighted the “association between response to T-cell engagers and a T-cell inflamed tumor microenvironment,” he said.
“The overall response rate observed in TP53-mutated patients [with AML] treated with flotetuzumab encourages further study of this immunotherapeutic approach,” concluded Rutella.