MD Anderson Research Highlights for February 9, 2022

Featuring findings in actionable gene fusions, cell therapies and targeted therapy for acute myeloid leukemia

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current advances include a classification system to identify clinically actionable gene fusions, an improved method to culture tumor-infiltrating lymphocytes for non-small cell lung cancer and an effective combination therapy for patients with acute myeloid leukemia carrying specific mutations.

Researchers develop approach to identify actionable gene fusions in cancer 

When chromosomes break or otherwise realign, gene fusions can result. Many gene fusions have been identified and successfully targeted in cancer — such as RET, BCR-ABL1 and NTRK fusions — but the functional impact and clinical relevance of most are unknown. Researchers led by Jun Li, Ph.D., and Han Liang, Ph.D., developed a functional genomics approach to systematically identify clinically actionable gene fusions in cancer using data from The Cancer Genome Atlas, which contains roughly 35,000 gene fusion events in more than 11,000 patient samples across 33 cancer types. Based on an analysis of related gene pathways and potential therapeutic targets, the researchers selected 110 fusions for in vitro and in vivo characterization. Focusing on the RTK-RAS signaling pathway, they identified several novel activating gene fusions, including ALK, RAF1, BRAF and FGFR3, that can affect drug sensitivity. Based on their findings, the researchers developed a classification system to prioritize gene fusions found in patient samples. Learn more in Science Advances.

New culture method improves TIL expansion for NSCLC treatments

Immune checkpoint inhibitors have transformed the treatment of non-small cell lung cancer (NSCLC), but many patients do not respond to the treatment or will have a disease recurrence. Therefore, researchers are interested in alternative forms of immunotherapy, such as tumor-infiltrating lymphocytes (TILs). This cellular therapy uses immune cells isolated directly from a patient’s tumor, and clinical studies in melanoma have shown TILs can prompt long-term responses. A research team led by Parin Shah, Marie-Andrée Forget, Ph.D., Meredith Frank and Chantale Bernatchez, Ph.D., developed a new, clinically scalable method for expanding NSCLC TILs that speeds manufacturing and enriches for anti-tumor CD8+ T cells. The new method cultures TILs with signals required for optimal T-cell activation: interleukin 2 (IL-2) plus antibodies that stimulate CD3 and 4-1BB. Compared with IL-2 alone, the new culture method increased TIL production more than fivefold and preserved the hierarchy and diversity of T cells found within the tumor. These findings offer new possibilities for evaluating TIL therapies in NSCLC. Learn more in the Journal for ImmunoTherapy of Cancer.

Combination therapy with venetoclax and azacitidine found effective against AML with specific mutations

Two studies published in Clinical Cancer Research by Courtney DiNardo, M.D., and Marina Konopleva, M.D., Ph.D., demonstrated that combination therapy with venetoclax and azacitidine has significant benefits for patients with acute myeloid leukemia (AML) carrying specific mutations. Their findings were pooled from a Phase III study comparing venetoclax and azacitidine with placebo and azacitidine, and a Phase Ib study in which patients were treated with venetoclax and azacitidine. Participants were treatment-naïve and ineligible for intensive therapy due to age (≥75 years) and/or comorbidities. From these studies, the researchers analyzed data from patients who had either a FLT3 mutation or an IDH1/2 mutation.

FLT3 mutations are typically associated with high leukemic burden and an increased risk of relapse; standard treatment is intensive chemotherapy. In the first study, FLT3 mutations were detected in 42 (15%) and 22 (19%) patients in each of the trials. Patients treated with a venetoclax and azacitidine combination experienced a 67% composite complete remission (CRc) rate and similar overall survival rates, regardless of FLT3 mutation status. However, improvement in overall survival in high risk FLT3-ITD mutated patients was not observed. No unexpected toxicities occurred. These findings suggest that treatment with venetoclax and azacitidine is an effective option for treatment-naïve patients ineligible for intensive chemotherapy, including those with FLT3 mutations.

In the second study, IDH1/2 mutations were detected in 81 (26%) and 28 (22%) patients in each of the trials. Of those, patients receiving venetoclax and azacitidine experienced a 79% CRc rate. Specifically, the CRc rate was 66.7% and 85% in those with an IDH1 mutation and IDH2 mutation, respectively. No unexpected toxicities were associated with venetoclax and azacitidine combination treatment. Overall, venetoclax and azacitidine together were found to produce high response rates, increased survival and durable remissions for patients with IDH1/2 mutations, especially those with IDH2 mutations.

Going forward, the researchers plan to evaluate “triplet regimens,” including FLT3-, IDH1- and IDH2-targeted therapeutics, as appropriate, to further improve outcomes in patients with specific mutations.

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