Precision chemo-immunotherapy for pancreatic cancer?

November 05, 2020

Pancreatic cancer is highly lethal: according to the National Cancer Institute, only about 10 percent of patients remain alive five years after diagnosis. Now, a preclinical study from the lab of Marsha Moses, PhD at Boston Children's Hospital, reports marked and lasting tumor regression in a mouse model, using a highly selective, potent, engineered antibody-drug combination.

The findings, published November 3 in the journal Advanced Science, provide the basis for further pre-clinical studies to advance this approach to the clinic, the researchers say.

Pancreatic cancer has proven very difficult to treat with drugs. Not only do the tumors have a limited blood supply, making it hard to deliver drugs, they are also surrounded by stroma (a dense connective tissue) and tumor cells are protected by an extracellular matrix (a meshwork of proteins and carbohydrates).

"It can be difficult to get drugs into these tumors," says Moses, who directs the Vascular Biology Program at Boston Children's. "We developed a novel chemo-immunotherapy agent that selectively recognizes and penetrates pancreatic tumors better than other therapeutics."

Led by Jing Huang, PhD, the Moses lab developed an antibody-drug conjugate, or ADC, consisting of two parts: an antibody that selectively homes to a molecule on the surface of pancreatic cancer cells, known as ICAM1, and a drug toxic to cancer cells. Cells bearing ICAM1 on their surface are killed by the drug, while normal cells are spared.

"The size of the ADC is similar to the size of a single antibody: less than 10 nanometers," says Peng Guo, PhD, of the Moses Lab, co-corresponding author on the paper with Moses. "Because of this ultra-small diameter, it can penetrate the stroma and reach pancreatic tumor cells better than other novel treatments such as T-cell immunotherapy or nanomedicines."

Rational selection of antibody and drug

The team chose ICAM1 as a target for the ADC antibodies after screening the tumor surface for dozens of different proteins. In 2014, the Moses lab showed high levels of ICAM1 on triple-negative breast cancers, and it is abundant on melanoma and thyroid cancers as well.

The team performed similarly unbiased screening to select the best drug to include in the ADC. from a pool of drugs already used clinically. They tested four candidate ADCs in two human pancreatic cancer cell lines as well as in normal pancreatic cells. ADCs combining ICAM1 antibodies with the cytotoxic drug DM1 (mertansine), used clinically in HER2-positive breast cancer, were the most effective in killing tumor cells, working better than other ADC drugs. The DM1-ICAM1 antibody combination did not harm non-cancerous pancreatic cells which do not produce ICAM-1.

Shrinking pancreatic tumors

The team next randomized mice with pancreatic tumors to receive one of four treatments, given as systemic injections: the DM1-ICAM1 antibody conjugate, DM1 bound to a non-targeting antibody (IgG), gemcitabine (a first-line chemotherapy drug used in pancreatic cancer), or a sham treatment.

Compared with the other groups, mice receiving the DM1-ICAM1 antibody conjugate had a significant reduction in tumor size that persisted during the 14-week study, even after just two doses. The treatment also effectively inhibited metastasis to normal organs including lung, liver, and spleen. There was no observed toxicity, assessed by weighing the animals and through pathology analysis of their organs.

Noninvasive tumor monitoring

Finally, Huang developed an MRI-based molecular tumor imaging technique to complement ICAM1 ADC therapy, confirming the presence of ICAM1 on the tumor without the need for an invasive biopsy. This could potentially help to predict the treatment's effect and monitor changes over time. Eventually, Moses hopes to be able to monitor the treatment effect using two non-invasive urinary biomarkers previously reported by the team.

While other ADCs have been tested in pancreatic cancer, none have shown sufficient efficacy in the clinic and have also resulted in off-target toxicity, says Moses. "The precision of our approach comes from both the specific targeting and the ability to monitor that targeting with MRI," she says.

The ICAM1-DM1 ADC is part of a portfolio of targeted, patented cancer drug delivery systems being developed in the Moses lab; others include nanolipogels, liposomes, and exosomes.
-end-
Jing Huang, PhD, of Boston Children's was first author on the paper. Agoston T. Agoston, MD, PhD of the Brigham and Women's Hospital was a coauthor. The study was supported by the Advanced Medical Research Foundation and the Karp Family Foundation.

Boston Children's Hospital

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.