Follicular lymphoma is a malignant tumor that forms in the lymphatic follicles from defective maturing B-lymphocytes. About a third of the diagnosed cases of this type of blood cancer are asymptomatic in the disease’s late stage.

Traditional treatment of follicular lymphoma combines the use of a monoclonal antibody drug-rituximab and antitumor chemotherapy. The duration of the primary treatment is 6-8 courses, followed by maintenance therapy-another 12 courses. Approximately 80% of patients achieve permanent remission. However, almost all of them relapse. Therefore, there is a clinical need for new methods of treatment.

A team of doctors from Italy and Australia investigated methods of stimulating antitumor immunity using an experimental vaccine injected into a tumor. The researchers evaluated the safety of the new treatment method and its clinical effectiveness.

Composition of the experimental antitumor vaccine

The main component of the vaccine is dendritic cells (DC) treated with interferon alpha-2b (IFN-A2B) and colony-stimulating protein complex (GM-CSF), which accelerates the synthesis of white blood cells after chemotherapy. For short, such dendritic cells are called IFN-DC.

Dendritic cells are a critical element of the immune system in cancer vaccination. First, they find and destroy cancer cells. Second, dendritic cells train other cells in the immune system to fight the tumor.

The effect of interferon-a2b on dendritic cells significantly increases their antitumor effectiveness. After this treatment, the dendritic cells:

  • multiply increase the synthesis of antitumor molecules;
  • more effectively train other cells in the immune system to recognize cancer cells;
  • more actively absorb tumor cells.

Cancer immunotherapy with IFN-DC is an applied and promising therapy for stimulating broader antitumor immunity.

The second component of the vaccine is rituximab. Its dose is significantly less than with traditional treatment. Rituximab is a drug of monoclonal antibodies made by genetic engineering. These antibodies help immune cells find tumor cells.

Preclinical studies

Before starting clinical trials, doctors studied the effectiveness of the vaccine’s component composition in cell cultures and mice.

First, the researchers compared the effectiveness of rituximab, IFN-DC, IFN-DC + rituximab. In the latter case, the ratio of IFN-DC to rituximab was 5:1. As a result, it was found that the combination therapy of IFN-DC + rituximab is 4 times more effective for killing follicular lymphoma cells than IFN-DC and 20 times more effective than rituximab (Figure A):

Image source: https://aacrjournals.org/clincancerres/article/25/17/5231/81661/Clinical-and-Antitumor-Immune-Responses-in

In a second preclinical experiment, the researchers conducted a study in mice to determine the ability of IFN-DC cells to complete maturation when pretreated with rituximab. Initially, the mice were injected with follicular lymphoma cells. After the lymphoma size reached 4 mm, the scientists injected 100 mcg of rituximab into the mice. A day later, 2 million IFN-DC cells were injected into the tumor. The treatment was repeated every 7 days, with a total of 3 injections. After 14 days, the researchers analyzed the size and composition of the tumor.

A study in mice showed that pre-treatment with rituximab contributed to the fact that within 24 hours, IFN-DC finished maturation and passed the stage of full activation. The researchers also studied how strongly IFN-DC and rituximab attract other immune cells to the tumor to destroy malignant cells. In the tumors of mice treated with rituximab or IFN-DC + rituximab, there were more CD8+ T-lymphocytes than in the control group of mice that did not receive treatment. It is noteworthy that in the mice that received an intra-tumor injection of IFN-DC, the destruction of the tumor occurred from the inside (Figure C, in the previous image).

The researchers concluded that intra-tumor IFN-DC activates the antitumor T-cell immune response and increases its strength.

Study design, patient selection, treatment regimen

The study involved 8 patients. All of them had a biopsy-confirmed follicular lymphoma, a low-tumor load, an adequate number of blood cells, and a life expectancy of more than 6 months. The study did not include patients with advanced lymphoma who require standard therapy, HIV-infected patients, patients with autoimmune diseases, and pregnant women.

In the first stage of the study, doctors grew IFN-DC for each patient. First, the scientists took the patient’s peripheral blood. Then white blood cells and monocytes were isolated from it. When the monocyte content reached 60%, the doctors began their cultivation for 3 days in an interferon-a2b and the colony-stimulating protein complex GM-CSF. The IFN-DCS grown in this way were collected, packaged in doses of 10 million molecules, and stored in liquid nitrogen until use.

The central part of the study was conducted from November 2014 to November 2017. The age of the patients ranged from 27 to 72 years. All patients had enlarged lymph nodes or had lesions larger than 1.5 cm in the areas available for local injections and treatment monitoring. All injections were made in one affected superficial lymph node. The remaining affected lymph nodes remained untreated to monitor the outcome.

At the beginning of each treatment cycle, patients were given a low dose of rituximab. After 24 hours, they were injected with 10 million IFN-DC cells. The first 4 cycles were conducted every 2 weeks, the subsequent 4 cycles monthly. All procedures were performed on an outpatient basis.

Study results

Treatment safety

All patients tolerated the treatment well. Only one patient had slight swelling and redness at the injection site. During the 26 months of follow-up, no one developed an autoimmune reaction.

Assessment of the clinical response

After the end of treatment, 4 study participants had a clinical response. 3 of them had a complete clinical response. Remission continues in 2 cases for 26 months.

In one patient, the tumor disappeared not only in the lymph node into which the injections were made but also in some other lymph nodes that were not treated. All lesions disappeared 13 months after the start of treatment. Remission has been going on for 27 months. This indicates the manifestation of a systemic effect of the treatment. The arrows show the affected areas before treatment, which disappeared after treatment:

Image source: https://aacrjournals.org/clincancerres/article/25/17/5231/81661/Clinical-and-Antitumor-Immune-Responses-in

 

Another patient underwent intensive pre-treatment before the study. After starting treatment with rituximab and IFN-DC, he achieved a complete clinical response after 6 months. The patient died after 22 months of remission as a result of treatment for acute myeloid leukemia.

Evaluation of antitumor T-cell responses

During the treatment, the doctors evaluated the biochemical parameters of the patients ‘ peripheral blood. It was found that higher levels of tumor-specific T-cell responses were observed in patients with a clinical response to treatment. The clinically unresponsive patient had a barely noticeable induction of the T-cell response.

Scientists conclude that treatment with rituximab and IFN-DC causes systemic antitumor T-cell responses.

Conclusions

The study demonstrated that combination therapy with IFN-DC and low-dose rituximab is safe and clinically justified for patients with follicular lymphoma who have undergone intensive treatment. IFN-DC is effective in inducing a clinical response and in stimulating the production of tumor-specific T cells.

The scientists emphasize that there was no radiation therapy in their treatment regimen, and one rituximab is enough to stimulate tumor antigens.

The study was conducted on a small sample of patients. Therefore, extensive cohort studies are needed to confirm the effectiveness of the method.

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Clinical and Antitumor Immune Responses in Relapsed/Refractory Follicular Lymphoma Patients after Intranodal Injections of IFNα-Dendritic Cells and Rituximab: a Phase I Clinical Trial

 

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