Chemo and immunotherapy
Cancer patients today have many treatment options available, but each of them has its drawbacks. Chemotherapy kills rapidly dividing cancer cells, but also damages healthy cells in the body and often does not prevent metastasis or relapses. Immunotherapy fights metastasis and relapses by affecting the patient's immune system and forming a stable anti-cancer response, but is often associated with problems accessing tumors due to the immunosuppressive environment that tumors create.
The new approach combines the advantages of two methods: the anti-cancer power of chemotherapy and the long-term effectiveness of immunotherapy. This new biomaterial-based vaccine can be administered directly next to the tumor. When mice with aggressive triple negative breast cancer were injected with the vaccine, 100% of them survived the subsequent injection of cancer cells without relapse. Triple negative breast cancer does not cause a strong reaction of the immune system, therefore, existing immunotherapeutic methods of treatment are ineffective. In the new vaccine, the immunotherapeutic component attracts numerous immune cells to the tumor, while the chemotherapeutic component gives a large number of fragments of dead cancer cells that immune cells can use to create an effective tumor-specific response.
Personalized vaccines without waiting
For the first time, an injectable anti-cancer vaccine was developed in 2009. She has shown great promise in the treatment of several types of cancer in mice and has been clinically tested for the treatment of melanoma at the Dana Farber Cancer Institute. In the initial version of the vaccine, the molecules found in cancer cells (tumor-associated antigens, TAA) were included together with adjuvants in the framework so that the arriving dendritic cells could recognize them as foreign and cause an immune response against the tumor. These TAAS can be isolated from collected tumors or identified by sequencing the genome of cancer cells and subsequently produced, but both of these processes to create personalized cancer vaccines are long, complex and expensive.
Source: The Wyss Institute at Harvard University.
One of the limiting factors in the development of cancer vaccines is the choice of TAA, because few antigens are currently known for specific tumor cell lines, and it is difficult to predict which of them can provide an effective immune response. Implantation of chemotherapeutic drugs into the vaccine framework causes a surge in cancer cell death, which releases TAA directly from the tumor into dendritic cells, bypassing the long and expensive process of antigen production.
The research team used this tactic to create a vaccine against triple negative breast cancer, a disease in which a tumor aggressively suppresses immune activity in its microenvironment, limiting the effectiveness of immunotherapy. To do this, the researchers first loaded granulocyte-macrophage colony stimulating factor (GM-CSF) into the hydrogel framework. The GM-CSF protein stimulates the development and accumulation of dendritic cells that capture antigens from tumors 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) attached to the iRGD peptide. iRGD is known to penetrate tumors and help target Dox to tumors after release.
The vaccine was tested on mice with triple negative breast cancer. Animals that received a scaffold loaded with GM-CSF and Dox-iRGD conjugate demonstrated significantly better penetration of the drug into tumors, increased cancer cell death and fewer metastatic tumors in the lungs than mice that received Dox gel or were not treated. The analysis of the scaffolds showed that a large number of dendritic cells had accumulated in them, which indicates the activity of both immunotherapeutic and chemotherapeutic components of the vaccine.
The scientists then added a third component to the vaccine– a synthetic bacterial DNA sequence (CpG), which is known to enhance the immune response. Mice given CpG vaccines showed significantly slower tumor growth and longer survival time than mice given vaccines without CpG. To assess the strength and specificity of the immune response caused by this three-component vaccine, the researchers extracted and analyzed cells from the lymph nodes and spleen of animals. Strikingly, 14% of T cells taken from lymph nodes reacted against tumor cells - indicating that they were "trained" by dendritic cells to target cancer – compared to only 5.3% of T cells in mice given the two–component vaccine and 2.4% of T cells from untreated mice. In addition, the administration of an additional dose of the vaccine 12 days after injection further increased their survival time.
Local action, long-term protection
When Dox (red) was bound to the tumor-infiltrating iRGD molecule, it effectively penetrated inside the tumor (blue) to attack them (left). Dox without this modification remained mainly in the hydrogel and did not migrate to tumors (right). Source: The Wyss Institute at Harvard University.
The group also wanted to understand how the vaccine affects the tumor microenvironment. The analysis showed that the cells in tumors treated with GM-CSF, Dox-iRGD and CpG gel contained an increased amount of calreticulin protein on their surface, which is an indicator of cell death. Mice that received the three-component vaccine also showed a greater number of pro-inflammatory macrophages, which are associated with anti-cancer activity and greater survival.
The researchers also found that the new treatment led to an increase in the expression of the PD-L1 surface protein on tumor cells, which is used to hide from the immune system. They assumed that co-administration of anti-PD-1, which blocks this protein, with a new vaccine would increase the effectiveness of the latter. They implanted a three-component vaccine into mice, and then separately injected anti-PD-1. Mice treated with a combination of the vaccine and anti-PD-1 showed significantly reduced tumor size and number and survived for an average of 40 days compared to 27 days in untreated mice and 28 days in mice that received only anti-PD-1. This synergy suggests that the vaccine is best used in combination with PD-1 inhibitors.
To mimic the way an anti-cancer vaccine is administered to humans, a group of researchers tested its ability to prevent cancer recurrence after removal of the primary tumor. They surgically excised tumors of triple negative breast cancer in mice, and then injected either a three-component hydrogel vaccine or a liquid vaccine containing all the components in suspension, near the original site of the tumor. In both treated groups, tumor recurrence was significantly lower, but the gel vaccine caused significantly slower tumor growth and improved survival. The mice were then re-injected with cancer cells, and 100% of the mice that received the gel vaccine survived without metastases, while all untreated mice died.
The ability of the new vaccine to elicit a strong immune response without the need to identify patient-specific antigens is a great advantage, as is the ability of local chemotherapy to act without severe systemic side effects. This vaccine not only activates dendritic cells with tumor-specific TAAS in situ, it also alters the tumor microenvironment to give the immune system greater access to the tumor, and creates immune memory that prevents further relapses.
The group continues to study the combination of chemotherapy with anti-cancer vaccines and hopes to improve their antitumor efficacy for other intractable tumor models. Scientists hope that future research to better understand and optimize the system will allow them to move on to preclinical trials and, eventually, to patients.
The newest version of the cancer vaccine is a multifunctional anti–cancer therapy that gives new hope for the treatment of a wide range of cancers. In fact, this is a completely new form of combined chemotherapy that can be administered with a single injection, and it potentially provides greater effectiveness with much less toxicity than traditional treatments used today.
Article H.Wang et al. Biomaterial-based scaffold for in situ chemo-immunotherapy to treat poorly immunogenic tumors published in the journal Nature Communications.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Wyss Institute: A viable vaccine for tough tumors.