Inmunologically active proteins on a T-cell: T-cell receptor, CD-4, CD-28, PD-1 and CTLA-4 and a calcium channel
Credit: selvanegra/Getty Images

Researchers from The University of Texas MD Anderson Cancer Center have developed a nanotechnology platform that can enhance the antitumor effect of immunotherapy in solid tumors by attaching an immune activation molecule to the surface of the tumors.

The universal nanobioconjugate platform, termed bispecific tumor-transforming nanoparticles (BiTNs) is the work of Wen Jiang, assistant professor of Radiation Oncology, Betty Kim, professor of neuroscience, and colleagues.

They initially developed the system to help promote tumor cell phagocytosis. “This platform was perfect to be adopted for our current study,” Jiang told Inside Precision Medicine. “One of the potential advantages of the nanobioconjugate system is that it allows multiple molecules to be attached on the nanoparticle, thus result in multiple receptor-ligand interactions (multivalency), hence enhance cell binding.”

The molecules attached to the nanoparticles for the current study were SLAMF7, short for signalling lymphocytic activation molecule family member 7, and an anti-human epidermal growth factor receptor (HER)2 antibody.

Jiang explained that it is already know that hematologic cancers respond better to immunotherapy than solid tumors and the team wanted to address this. “Searching in the literature we saw that SLAMF7 was reported to be an ‘eat me’ signal that was only expressed by blood cells and not in solid tumors and its expression was critical for the body’s immune cells to clear cancer cells,” he said. “Therefore, we thought what if we could artificially put the SLAMF7 onto the surface of solid tumor cells, would it help the immune system detect and eliminate them?”

They tested their hypothesis in breast cancer cells that expressed HER2 on the surface and found that, through the anti-HER2 antibody, the BiTNs showed selective targeting towards HER2-overexpressing human and mouse breast cancer cells. This in turn allowed the successful SLAMF7 labelling of these cells and increased phagocytosis by macrophages.

The approach also sensitized the breast cancer cells to treatment with an anti-CD47 antibody, which blocks the ‘don’t eat me’ signal from tumor cells to further increase responses in solid tumors. Similar results were observed when the researchers tested the BiTNs in a mouse model of breast cancer.

They write in Nature Nanotechnology that the results “indicate that the targeted transformation of HER2 [high-expressing] breast cancer cells into a SLAMF7 [high-expressing] phenotype is essential to initiate phagocytosis by macrophages.”

They add that the transformation in to SLAMF7 high-expressing tumors in mice promotes tumor-specific activation of local innate immune responses and “further supports the finding that SLAMF7 ligation physically triggers macrophage activation and synergistically promotes CD47 blockade to bridge the innate and adaptive immune systems and enhance the elimination of tumor cells.”

Jiang and team also tested the BiTNs in combination with PD-1 blockade – an immunotherapy approach used in the treatment of many solid tumors.

They found that although the combination of BiTNs plus anti-PD-1 was no more effective at inhibiting tumor growth than anti-PD-1 alone, the combination of BiTNs plus anti-CD47 and anti-PD-1 was superior to anti-CD47 and anti-PD-1 without the BiTNs.

This suggests that BiTN needs to have CD47 blockade in place to work, said Jian. He added that once the phagocytosis begins, it will start to improve the T cell responses mediated by PD1 blockade. “In the clinical setting, we do envision BiTN or its derivatives to be given in combination with CD47 and PD-1 blockade to produce the optimal effect.”

The investigator believes that the BiTN strategy could be eventually used to design targeted immunotherapy for patients as the molecular target can easily be changed from HER2 to another tumor-specific protein such as folate or EGFR.

The next steps will now be to try and translate the BiTN or its derivative into the clinic. “One strategy we are thinking of is to develop a protein-based derivative of BiTN,” noted Jiang. “This allows us to address some of the manufacturing and toxicity issues associated with the nanoparticles which are in the core of BiTN. The protein based BiTN would be similar to other bispecific antibodies or engagers out there.”

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