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Developmental Biology - CAR T-cell Therapy

Alpacas Could Help CAR T-cell Therapy

'Nanobodies' from alpacas could help bring CAR T-cell therapy to human solid tumors...


In 1989, two undergraduate students at the Free University of Brussels were asked to test frozen blood serum from camels. While doing so, they stumbled on a previously unknown kind of antibody. It was a miniaturized version of a human antibody, made up only of two heavy protein chains, rather than two light and two heavy chains typically found in humans. As they eventually reported, the antibodies' presence was confirmed not only in camels, but also in llamas and alpacas.

Fast forward 30 years. This week in the journal PNAS, researchers at Boston Children's Hospital and MIT reveal how these mini-antibodies shrunk further to create so-called nanobodies may help solve a problem in the cancer field: making CAR T-cell therapies effectve against solid tumors.
Highly promising for blood cancers, Chimeric Antigen Receptor or (CAR) T-cell therapy genetically engineers a patient's own T cells to make them better at attacking cancer cells.

The Dana-Farber/Boston Children's Cancer and Blood Disorders Center is currently using CAR T-cell therapy with relapsed Acute Lymphocytic Leukemia (ALL) patients.

However, CAR T-cells haven't been good at eliminating solid tumors. It's been hard to find cancer-specific proteins on solid tumors that serve as safe targets. Solid tumors are protected by an extracellular matrix made up of a web of proteins acting as a protective barrier; as well as by immuno-suppressive molecules that weaken any T-cell attack.

Rethinking CAR T-cells

This is where nanobodies can help. For two decades, nanobodies largely remained in the hands of the Belgian team who found them. But that changed after the Belgian patent ended in 2013. "A lot of people then got into the game and began to appreciate nanobodies' unique properties," explains Hidde Ploegh PhD, immunologist, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and senior investigator on the PNAS study.

One useful attribute is their enhanced targeting ability. Ploegh and his team at Boston Children's, in collaboration with Noo Jalikhani PhD and Richard Hynes PhD at MIT's Koch Institute for Integrative Cancer Research, have harnessed nanobodies to carry imaging agents, allowing precise visualization of metastatic cancers. The Hynes team tagged nanobodies onto a tumors' ExtraCellular Matrix, or ECM - aiming imaging agents not at the cancer cells themselves, but at their surrounding environment. Such markers are common on many tumors, but don't typically appear on normal cells.
"Our lab and the Hynes lab are among the few actively pursuing targeting the tumor micro-environment. Most labs are looking for tumor-specific antigens."

Hidde Ploegh PhD, Senior Investigator, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

Targeting Tumor Protectors

Ploegh's team, including members of the Hynes lab, applied the idea to CAR T-cell therapy. The CAR T cells they created were studded with nanobodies that recognize specific proteins in the tumor environment, bearing signals directing them to kill any cell they bound to. One protein, EIIIB, a variant of fibronectin, is found only on newly formed blood vessels that supply tumors with nutrients. Another, PD-L1, is an immunosuppressive protein that most cancers use to silence approaching T cells.

Biochemist Jessica Ingram PhD, of the Dana-Farber Cancer Institute, Ploegh's partner and a coauthor on the paper, led the manufacturing pipeline. She would drive to Amherst, Mass., to gather T cells from two alpacas, Bryson and Sanchez, inject them with the antigen of interest and harvest their blood for further processing back in Boston to generate mini-antibodies.

Taking Down Melanoma and Colon Cancers
Tested in two separate melanoma mouse models, as well as a colon adenocarcinoma model in mice, the nanobody-based CAR T cells (1) killed tumor cells, (2) significantly slowed tumor growth and (3) improved the animals' survival, with no readily apparent side effects.

Ploegh thinks that the engineered T cells work through a combination of factors. They caused damage to tumor tissue, which tends to stimulate inflammatory immune responses. Targeting EIIIB may damage blood vessels in a way that decreases blood supply to tumors, while making them more permeable to cancer drugs.
"If you destroy local blood supply, causing vascular leakage, you perhaps improve delivery of other things that might have a harder time getting in. I think we should look at this as part of a combination therapy."

Hidde Ploegh PhD

Future Directions

Ploegh thinks his team's approach could be useful in many solid tumors. He's particularly interested in testing nanobody-based CAR T cells in models of pancreatic cancer and cholangiocarcinoma, a bile duct cancer from which Ingram passed away in 2018.

"The technology can be pushed even further. Nanobodies could potentially carry a cytokine to boost the immune response to the tumor, toxic molecules that kill tumor and radioisotopes to irradiate the tumor at close range," Ploegh explains. "CAR T cells are the battering ram that would come in to open the door; the other elements would finish the job. In theory, you could equip a single T cell with multiple chimeric antigen receptors and achieve even more precision. That's something we would like to pursue.

Significance
Despite its success in treating hematological cancers, chimeric antigen receptor (CAR) T-cell therapy does not so easily eliminate solid tumors. Solid tumors generally develop in a highly immunosuppressive environment and are difficult to target, mostly due to a lack of tumor-specific antigen expression, but other factors contribute as well. This study develops a strategy to target multiple solid tumor types through markers in their microenvironment. The use of single-domain antibody (VHH)-based chimeric antigen receptor (CAR) T-cells that recognize these markers circumvents the need for tumor-specific targets. VHH-based CAR T-cells that target the tumor microenvironment through immune checkpoint receptors or through stroma and ECM markers are effective against solid tumors in syngeneic, immunocompetent animal models.

Abstract
Chimeric antigen receptor (CAR) T cell therapy has been successful in clinical trials against hematological cancers, but has experienced challenges in the treatment of solid tumors. One of the main difficulties lies in a paucity of tumor-specific targets that can serve as CAR recognition domains. We therefore focused on developing VHH-based, single-domain antibody (nanobody) CAR T-cells that target aspects of the tumor microenvironment conserved across multiple cancer types. Many solid tumors evade immune recognition through expression of checkpoint molecules, such as PD-L1, that down-regulate the immune response. We therefore targeted CAR T-cells to the tumor microenvironment via the checkpoint inhibitor PD-L1 and observed a reduction in tumor growth, resulting in improved survival. CAR T-cells that target the tumor stroma and vasculature through the EIIIB+ fibronectin splice variant, which is expressed by multiple tumor types and on neovasculature, are likewise effective in delaying tumor growth. VHH-based CAR T-cells can thus function as antitumor agents for multiple targets in syngeneic, immunocompetent animal models. Our results demonstrate the flexibility of VHH-based CAR T-cells and the potential of CAR T-cells to target the tumor microenvironment and treat solid tumors.

Authors
Yushu Joy Xie, Michael Dougan, Noor Jailkhani, Jessica Ingram, Tao Fang, Laura Kummer, Noor Momin, Novalia Pishesha, Steffen Rickelt, Richard O. Hynes, and Hidde Ploegh.


Acknowledgements
Yushu Joy Xie, a graduate student in Boston Children's Program in Cellular and Molecular Medicine and MIT's Koch Institute, was first author on the paper. Supporters include the Lustgarten Foundation, the National Science Foundation, the National Institutes of Health, the American Gastroenterological Association, the Howard Hughes Medical Institute Department of Defense and the National Cancer Institute. See the paper for details on authors and funders.


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Apr 17 2019   Fetal Timeline   Maternal Timeline   News  




Bryson and Sanchez, the two alpacas who produce unusually small antibodies. Their 'nanobodies' help highly promising CAR T-cell therapies kill solid tumors. CREDIT: Boston Children's Hospital.


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