Biomaterial-based cancer vaccines combine chemotherapy and immunotherapy to treat triple-negative breast cancer

Cancer patients have multiple treatment options available today, but each has its drawbacks. Chemotherapy kills rapidly dividing cancer cells, but it also damages healthy cells in the body and cannot effectively prevent tumor metastasis or recurrence of the disease. Immunotherapy avoids these problems by acting on the patient’s immune system to cause a persistent anticancer response, but problems with access to the tumor due to the immunosuppressive local environment it creates. Often occurs.

Currently, the new, best-of-breed approaches in both worlds are packaging the cancer-killing power of chemotherapy and the long-term efficacy of immunotherapy into biomaterial-based cancer vaccines that can be injected adjacent to the tumor site. ..For aggressive mice Triple negative breast cancer (TNBC) were vaccinated and 100% of them survived subsequent injections of cancer cells without recurrence.This study is reported in Nature Communications..

“Triple negative breast cancer did not stimulate a strong response from the immune system, and existing immunotherapies could not treat it. In our system, immunotherapy attracts a large number of immune cells to the tumor, and chemotherapy is numerous. It produces dead cancer cell fragments that immune cells can pick up and use to produce effective tumor-specific responses. ” Co-lead authors Hua Wang, Ph.D. .. Currently, Paulson School of Applied Sciences (SEAS) is an assistant professor in the Faculty of Materials Science and Engineering at the University of Illinois at Urbana-Champaign.

Personalized vaccine without waiting

The injectable cancer vaccine, first developed in 2009, holds great promise for the treatment of multiple types of cancer in mice and is being investigated in clinical trials at the Dana Farber Cancer Institute to treat melanoma. .. In the original formulation of the vaccine, molecules found in cancer cells called tumor-related antigens (TAAs) were integrated into aspirin-sized scaffolds with adjuvants, and dendritic cells that arrived recognized them as “foreign.” , Allowed to initiate a targeted immune response. For tumors. These TAAs can be isolated from harvested tumors or sequenced, identified, and then produced in the genome of cancer cells, but both of these processes to create a personalized cancer vaccine are long. , Cumbersome and can be expensive.

“One of the key limiting factors in the development of cancer vaccines is the choice of TAA, which currently has a very small library of known antigens for some specific tumor cell lines, which is effective immunity. It’s difficult to predict if you’ll get a response. ” Co-lead author Alex Najibi is a graduate student in Wiscore’s faculty, David Mooney’s lab. “Transplanting a chemotherapeutic drug into a vaccine scaffold causes a burst of cancer cell death, releasing TAA directly from the tumor into dendritic cells, bypassing the long and costly antigen development process.”

Wang, Najibi, and their colleagues have attempted to apply this new cancer vaccine tactic to TNBC. It is a disease in which the tumor actively suppresses local immune activity, limiting the effectiveness of immunotherapy. The team first loaded a protein molecule called granulocyte-macrophage colony stimulating factor (GM-CSF) onto a hydrogel alginate scaffold. GM-CSF stimulates the development and concentration of dendritic cells. Dendritic cells take up antigens from tumors and other invaders and present them to T cells in the lymph nodes and spleen to initiate an immune response. They also added the chemotherapeutic drug doxorubicin (Dox), which is bound to a peptide called iRGD. iRGD is known to penetrate tumors and helps target Dox to tumors upon release.

When new vaccines were injected into mice with TNBC tumors, mice that received a scaffold loaded with GM-CSF and Dox-iRGD conjugates had significantly improved drug penetration into the tumor, increased cancer cell death, and increased cancer cell death. The number of metastatic tumors in the lung has decreased. Than those who received a gel containing Dox bound to a scrambled peptide molecule, unmodified Dox, or untreated.Scaffold analysis shows that they have accumulated a large number of dendritic cells, both Immunotherapy The chemotherapeutic component of the vaccine was active.

Encouraged by these results, the team then experimented with adding a third component to a vaccine called CpG, a synthetic bacterial DNA sequence known to enhance the immune response. Mice vaccinated with this additive had significantly slower tumor growth and longer survival than mice vaccinated without it. To assess the strength and specificity of the immune response produced by this three-part vaccine, researchers extracted and analyzed cells from the lymph nodes and spleen of animals. Surprisingly, 14% of T cells collected from the lymph nodes responded to tumor cells, causing cancer by dendritic cells compared to only 5.3% of mice receiving the two-part vaccine. Indicates that you have been “trained” to target. 2.4% of untreated mouse T cells. In addition, 12 days after the injection, a “booster” dose of the vaccine was given for even longer survival.

Localized action, long-term protection

These results revealed the effect of the vaccine on immune system activation, but the team also wanted to understand how it affected the local tumor microenvironment. Analysis of the vaccine and nearby tumors shows that tumor cells treated with gels containing GM-CSF, Dox-iRGD, and CpG have increased levels of the protein calreticulin, an indicator of cell death. It became clear. Mice vaccinated with the three-part vaccine also had a higher number of pro-inflammatory macrophages. These are white blood cells that are associated with improved anticancer activity and prolonged survival.

Researchers also found that their treatment caused increased expression of the cell surface protein PD-L1 on tumor cells. It is used by cancer to avoid immunoassays. They had the feeling that co-administration of anti-PD-1 checkpoint inhibitor therapy to prevent this immune evasion with the vaccine would increase its effectiveness. They transplanted a three-part vaccine into mice and then injected anti-PD-1 separately. Mice treated with the gel vaccine plus anti-PD-1 significantly reduced tumor size and number in 27 days in untreated mice and 28 days in mice treated with anti-PD-1 alone. In contrast, the median survived for 40 days. .. This synergistic effect suggested that the vaccine may be best used in combination with checkpoint inhibitor therapy.

To mimic how a cancer vaccine is given to human patients, the team tested its ability to prevent the recurrence of cancer after the primary tumor has been removed. They surgically resected the TNBC tumor from the mice and injected either a three-component hydrogel vaccine or a liquid vaccine containing all the ingredients in a suspension near the original tumor site. Tumor recurrence was significantly lower in both treatment groups, but the gel vaccine significantly slowed tumor growth and improved survival. Mice were then injected with cancer cells and re-challenged, and surprisingly, 100% of the gel-vaccinated mice survived without metastasis, but all untreated mice died of the disease. Did.

“The ability of this vaccine to elicit a strong immune response without the need to identify patient-specific antigens is a major advantage, as is the ability to deliver local chemotherapy to avoid the serious side effects of systemic chemotherapy. I’m sick. ” The corresponding author, Dr. Mooney, leads the Wis Institute’s Immunomaterials Platform and is also Professor Robert P. Pincus Family of SEAS. “This vaccine not only activates dendritic cells in situ using tumor-specific TAA, but also reshapes the tumor microenvironment, making the immune system more accessible to the tumor and creating immune memory. Prevents further recurrence. “

The team continues to investigate the combination of chemotherapy and cancer vaccines and hopes to improve its antitumor effect on other difficult-to-treat tumor models. The team hopes that future research to better understand and optimize the system will allow it to move to preclinical studies and ultimately to human patients.

“The team’s latest version of the cancer vaccine is a new multifunctional anti-cancer therapy that brings new hope for the treatment of a wide range of cancers. It is essentially a whole new form that can be administered in a single injection and can potentially be offered. Ingber is a professor of vascular biology at Harvard University School of Medicine, Boston Children’s Hospital, with much lower toxicity and higher efficacy than traditional treatments used today. He is also a professor of vascular biology program and bioengineering of SEAS.