The first patient has been dosed in the Phase 1 Trial of SEL-403. This trial uses a drug that combines nanoparticles containing rapamycin (SVP-R)—a drug that controls cell growth—with the protein-based drug LMB-100 in order to treat tumors caused by pleural or peritoneal mesothelioma.

Earlier studies have shown that recombinant immunotoxins (molecules that kill cancer cells) like LMB-100 are effective at treating tumors. However, success is limited by antidrug antibodies (ADAs)—the body’s immune system response against certain drugs.

SVP-R aims to prevent the body from producing ADAs and stop the protein-based drugs from being neutralized so the drugs can continue to fight off the tumors.

Preclinical trials of SEL-403 have shown that this combination is not only effective in mice who do not have any ADAs, but also in mice who have pre-existing antibodies.

This finding bodes well for patients who already have the anti-drug antibodies in their system.

First Patient Dosed in Phase 1 Trial

The study, conducted by Selecta Biosciences in Watertown, MA, is expected to recruit 18 participants. These patients are individuals who are suffering from either malignant pleural or peritoneal mesothelioma, and who have already undergone at least one round of chemotherapy.

This trial is being conducted under a Cooperative Research and Development Agreement (CRADA), with the National Cancer Institute (NCI), part of the National Institutes of Health.

Dr. Raffit Hassan, the Senior Investigator of the Thoracic and GI Oncology Branch in NCI’s Center for Cancer Research and Principal Investigator of the trial, said in a press release:

Mesothelioma remains one of the deadliest and most challenging-to-treat forms of cancer. Recombinant immunotoxins hold the potential to induce marked anti-tumor activity if anti-drug antibodies are prevented and sufficient cycles of therapy can be administered. We are pleased to get this clinical investigation underway to determine if patients may indeed benefit from a combination therapy consisting of LMB-100 and SVP-Rapamycin.

Participants in the phase 1 trial will receive up to 4 treatment cycles.

On the first day of each treatment cycle, the patients will receive an initial dose of SVP-R and LMB-100. Then on days 3 and 5, the patients will receive 2 doses of just LMB-100.

The goal is to determine how safe and tolerable this treatment is, provide data on pharmacokinetics (the study of drugs moving through the body) and anti-drug antibody levels and assess how well patients respond to treatment.

Outlook for Mesothelioma—Will the Treatment Be Effective?

SEL-403 is a combination of the two drugs, SVP-R and LMB-100.

SVP-R: SVP-R is Selecta Biosciences clinical-stage ADA prevention and immune tolerance technology. It is an immunomodulator encapsulated in a nanoparticle delivery system—meaning a chemical agent that modifies the immune system and is administered as tiny particles.

SVP-R is designed to induce a specific immune tolerance which will prevent the formation of ADAs. This is important for patients because it means that their own bodies will stop working against their cancer treatment plans.

LMB-100: LMB-100 is a recombinant immunotoxin or protein-based drug. It specifically targets the protein mesothelin, a substance present in almost all mesothelioma patients.

Recombinant immunotoxins are proteins that are effective at treating cancer, specifically when the patients’ immunity is suppressed, as it is for patients with leukemia. However, in cancers like mesothelioma where the patients’ immune system isn’t suppressed, recombinant immunotoxins induce the formation of ADAs.

These anti-drug antibodies attack the protein-based drugs and neutralize them, which prevents the recombinant immunotoxins like LMB-100 from reducing tumors.

So when LMB-100 is used in combination with SVP-R, the hope is that the ADA prevention and immune tolerance technology of SVP-R will cooperate together to build an immune tolerance to immunotoxins, such as LMB-100.

This immune tolerance will prevent the formation of ADAs, meaning that the mesothelioma patient’s body will no longer fight to neutralize the beneficial drugs. Therefore, the protein-based drug will once again be able to reduce the size of the patient’s tumors.

While this drug combination remains in phase 1 of its clinical trial, it shows promise that researchers are better understanding the relationship between a mesothelioma patient’s body and the novel immunotherapy drugs being developed.

View Author and Sources
Author

Sources
  1. Ronit Mazor, et al. “Tolerogenic nanoparticles restore the antitumor activity of recombinant immunotoxins by mitigating immunogenicity” Proceedings of the National Academy of Sciences Jan 2018, 115 (4) E733-E742; DOI: 10.1073/pnas.1717063115. Retrieved from: http://www.pnas.org/content/115/4/E733 Accessed March 20, 2018.
  2. Globe Newswire, “Selecta Biosciences Announces First Patient Dosed in Phase 1 Trial of SVP-Rapamycin and LMB-100 Combination Therapy in Mesothelioma.” Retrieved from: http://www.globenewswire.com/news-release/2018/03/12/1420496/0/en/Selecta-Biosciences-Announces-First-Patient-Dosed-in-Phase-1-Trial-of-SVP-Rapamycin-and-LMB-100-Combination-Therapy-in-Mesothelioma.html. Accessed March 20, 2018.

Last modified: April 4, 2019