Experimental drug summons 'immune system warriors,' early promise v. non-Hodgkin lymphoma

 An investigational therapy is demonstrating preclinical promise against non-Hodgkin lymphoma by boosting natural killer cells and efficiently annihilating the malignancy without toxicity to the patient, a team of cancer biologists in France has found.

The emerging therapy is for B cell non-Hodgkin lymphoma, the most common form of lymphoma worldwide. Current therapies target the CD20+ protein on the surface of cancerous B cells but with limited efficacy. A newly developed antibody-based molecule targets B-non-Hodgkin lymphoma by engaging natural killer cells, warriors of the immune system. The experimental therapeutic is expected to help patients whose disease rebounds and is difficult to treat.

"Non-Hodgkin lymphoma is the most frequent hematological malignancy in humans, comprising nearly 3% of all cancer diagnoses and oncology-related mortalities," writes Dr. Olivier Demaria, lead author of the research published in Science Immunology.

"The therapeutic landscape for relapsed or refractory B-cell non-Hodgkin lymphoma has recently undergone a major transformation with the advent of CD19-targeted autologous CAR-T cell therapies," continued Demaria, a cancer immunologist at Innate Pharma Research Laboratories in Marseille, France.

"However, these therapies come with notable challenges. The production of autologous CAR-T therapies is intricate, involving sophisticated manufacturing processes and logistical complexities."

Demaria and colleagues are testing a molecule that they call a tetra-specific natural killer cell engager, which for now goes by its investigational name, IPH6501. The team at Innate Pharma Research Laboratories is currently evaluating tests of IPH6501 in relapsed non-Hodgkin lymphoma patients. But much of the work to prove that the molecule is a potent force against the cancer has been conducted in cell lines and animal models.

The molecule itself has four components, including three that activate natural killer cells. An additional anti-CD20 antibody fragment directly targets the cancer. By design, the molecule possesses an interleukin-2 variant that triggers natural killer cell proliferation without activating regulatory T cells.

Activation of regulatory T cells is a common occurrence in T cell-engager treatments, which can lead to therapy resistance. The researchers also produced a variant of the molecule, called CD20-NKCE-IL2v, with a key change in one domain to enable testing in mouse models.

The team has tested this tetra-specific molecule in the laboratory in mice and non-human primates, as well as in human cell lines of non-Hodgkin lymphoma. Scientists have confirmed that natural killer cell activation is effective. The molecule so far appears to have powerful potential as a B-cell non-Hodgkin lymphoma therapeutic, Demaria and colleagues say.

"Natural killer cells offer a promising alternative to T cell therapies in cancer," added Demaria, noting that further tests of IPH6501 are planned. Among the intriguing features of the molecule that have emerged so far is IPH6501's capacity to induce natural killer cell homing at the tumor site.

The French research arrives as medical scientists are deeply involved in a worldwide race to develop better treatments for non-Hodgkin lymphoma. There are more than 60 different subtypes of disease, which are classified based on the type of lymphocyte that the cancer affects—B cells or T cells. B cell lymphomas rank as the most common globally.

To make a diagnosis of non-Hodgkin lymphoma, a pathologist studies patients' cells under a microscope, taking note of their appearance and other critical features, such as how fast the cancer is growing. In the United States, non-Hodgkin lymphoma is the sixth most common cancer in both men and women.

While current treatments are effective, aggressive and recurrent forms of the disease can elude even the best therapies. Teams of researchers in Europe and the United States are particularly focused on developing targeted therapies and immunotherapies, to expand the treatment armamentarium for patients. IPH6501 is an experimental immunotherapy that harnesses the power of natural killer cells.

"Natural killer cells are innate lymphoid cells that have the inherent capability to identify and destroy malignant cells with their effectiveness being particularly notable in hematologic malignancies," Demaria added. "Elevated natural killer numbers have been correlated with improved responses."

In the laboratory, treating animal models with IP6501 produced higher efficacy and lower toxicity than existing B-cell non-Hodgkin lymphoma therapies. The French team found that IPH6501 produced encouraging results in mouse models and non-human primates.

Novel non-Hodgkin lymphoma treatments, such as T cell engagers which are also antibody-based molecules, have shown clinical promise but can cause serious toxicities.

"[Our] natural killer cell engager represents an innovative approach in cancer immunotherapy that harnesses natural killer cells as an alternative to existing T cell-directed treatments," Demaria concluded.

More information: Olivier Demaria et al, A tetraspecific engager armed with a non-alpha IL-2 variant harnesses natural killer cells against B cell non-Hodgkin lymphoma, Science Immunology (2024). DOI: 10.1126/sciimmunol.adp3720

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