ASCO: Emerging approaches to improve immunotherapy for cancer treatment

Brian Odle has now overcome four cancer diagnoses in his life, thanks to inheriting a mutation in the TP53 gene. This inherited condition is known as Li-Fraumeni Syndrome and puts carriers at an increased risk of several cancer types.

By summer 2019, Brian had been successfully treated for a large germ cell tumor, melanoma and osteosarcoma. However, that summer he began feeling poorly, and his MD Anderson care team ordered a bone marrow biopsy during a routine follow-up appointment.

It was then his doctors discovered he had myelodysplastic syndrome (MDS), a form of pre-leukemia, requiring him to have regular infusions of blood products. By August, he was bedridden and in need of a more effective treatment option. He decided to enroll on a clinical trial testing an immunotherapy called magrolimab. Since enrolling on the trial, he’s had a strong response and significantly improved his quality of life.

“I was no longer bedridden. I was able to get out and about and work again,” says Brian. “If this hadn’t been available when I was diagnosed, I’m not sure I’d still be here today. I only hope it’s done the same for others.”

Immunotherapy is designed not to attack the cancer, but rather to improve the immune system’s ability to eliminate the disease. Immune-based therapies can take many forms, including immune checkpoint inhibitors and adoptive cellular therapy, which stimulate the immune system in different ways.

Studies presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting by MD Anderson researchers showcase data on new immunotherapies and approaches to enhance the effectiveness of existing treatment options.

Anti-CD47 checkpoint inhibitor plus chemotherapeutic azacitidine appears effective in MDS and AML (abstract 7507)

CD47 is an immune checkpoint molecule found in macrophages, or white blood cells, and is used by leukemia cells to prevent detection by the immune system. Magrolimab is an antibody designed to inhibit CD47, much like other checkpoint blockade therapies, leading to elimination of leukemia cells.

A Phase Ib clinical trial is currently investigating the therapy in combination with the chemotherapy azacitidine for patients with acute myeloid leukemia (AML) or high-risk MDS, and updated data from the trial was presented at ASCO. Naval Daver, M.D., associate professor of Leukemia, is senior author and national co-leader of the clinical trial.

The combination has shown encouraging clinical activity, explains Daver, particularly in frontline high and very-high risk MDS and patients with TP53-mutant AML. The combination resulted in objective responses in 91% of patients with MDS, including 42% complete response. These responses improved over time, with 56% of patients who had greater than six-month follow up achieving a complete response.

In patients with AML, 64% saw an objective response, including 40% with a complete response. In particular, 75% of patients with TP53 mutations observed a complete response or complete response with incomplete hematologic recovery.

These data compare favorably with historical response rates for these patients with azacitidine alone or intensive chemotherapy, says Daver, and the combination was well-tolerated.

Full information on co-authors and disclosures for these studies is available here.

Bispecific T cell engager molecule AMG 330 shows early clinical activity in advanced acute myeloid leukemia (abstract 7508)

Bispecific Tcell engagers (BiTE) are immune therapies designed to enhance the anti-tumor activity of T cells in a patient. These molecules consist of two fused antibody segments, one to bind molecules on the T cell and one to bind molecules on the cancer cell to bring the cells in closer proximity.

AMG 330 is a BiTE therapy that binds the CD33 protein on leukemia cells and CD3 protein on T cells. It is currently under investigation in a Phase I dose-escalation study for patients relapsed or refractory AML. Updated results from the trial were presented by Farhad Ravandi, M.D., professor of Leukemia.

Of 42 patients able to be evaluated on the trial, eight (19%) responded, including three complete remissions and four complete remissions with incomplete count recovery. Responses to the therapy corresponded with higher doses of AMG330.

All patients experienced some treatment-related adverse events, with the most common being cytokine release syndrome. Cytokine release syndrome was reversible and corresponded to dose level of the treatment.

Full information on co-authors and disclosures for these studies is available here.

Dual checkpoint inhibitor molecule achieves partial responses in multiple cancer types (abstract 3004)

Checkpoint inhibitors act by binding immune checkpoint molecules and blocking signals that prevent the immune system from eliminating cancer. A new therapy, known as MGD103, is designed to simultaneously bind two immune checkpoint molecules, PD-1 and LAG-3, on T cells to enhance their anti-tumor activity.

MDG103 is being evaluated in a Phase I clinical trial for patients with advanced cancers, and updated results from the study were presented. George Blumenschein, M.D., professor of Thoracic/Head and Neck Medical Oncology, is senior author on the study.

In 41 patients, the therapy achieved three partial responses in patients with triple-negative breast cancer, mesothelioma and stomach cancer. Additionally, 21 patients had stable disease. Expansion cohorts on the trial also have seen further partial responses in patients with ovarian cancer and triple-negative breast cancer.

In six patients with tumors expressing the protein HER2, a combination of MDG103 and the HER2 antibody margetuximab resulted in three partial responses and two patients with stable disease.

Treatment-related adverse events were primarily below grade 3, with most common side effects being fatigue and nausea. Immune-related adverse events were consistent with treatment on PD-1 checkpoint inhibitors.

Full information on co-authors and disclosures for these studies is available here.

Mutations in POLE gene associated with clinical benefit from immune checkpoint inhibitors (abstract 3008)

Despite the success of immune checkpoint inhibitors in cancer medicine, responses are not consistent across patients or cancer types. In an effort to identify promising biomarkers that can identify patients who will respond to checkpoint inhibitors, research led by Benjamin Garmezy, M.D., hematology/oncology fellow, and Timothy Yap, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics, analyzed genetic data from MD Anderson patients who received these therapies.

Mutations in the DNA polymerase epsilon (POLE) gene are known to cause errors in DNA replication, which increase mutation rates in the DNA. These accumulated mutations may help the immune system to better recognize a tumor as abnormal and more effectively eliminate it.

The researchers analyzed DNA sequencing data from nearly 13,000 patients to evaluate POLE mutations and correlated their findings with patient benefit to immune checkpoint blockade therapy. Data were presented by Garmezy.

Of the patients analyzed, 448 (3.5%) had an alteration in the POLE gene, and clinical data were available for 293 of those patients. The most common cancers included were colorectal cancer, non-small cell lung cancer, cholangiocarcinoma and melanoma. The researchers also analyzed co-occuring mutations in other known cancer-related genes and biomarkers such as PD-L1, microsatellite instability (MSI) status and tumor mutation burden.

Their findings suggest that mutations in POLE correspond with an improved clinical benefit from anti-PD-1 and/or anti-PD-L1 checkpoint inhibitors. Additional studies are needed to confirm these findings, but the researchers are cautiously optimistic that POLE mutations may have value as a putative predictive biomarker of response.

Full information on co-authors and disclosures for these studies is available here.