Therapy Combination May Have Value as a Treatment For Slow-Growing B-Cell Lymphomas

People with slow-growing B-cell lymphomas and no symptoms are often prescribed a watch-and-wait approach, which involves monitoring until the disease grows and warrants treatment.
BY Beth Fand Incollingo
PUBLISHED October 29, 2018
People with slow-growing B-cell lymphomas and no symptoms are often prescribed a watch-and-wait approach, which involves monitoring until the disease grows and warrants treatment.
But for many, the idea that cancer has been identified, yet is not being treated, is maddening.

There are reasons for the strategy, a main one being the desire to avoid unpleasant side effects in people whose disease does not yet require treatment, according to Cancer Currents, a blog published by the National Cancer Institute (NCI). The chemotherapy and targeted drugs available can, in fact, cause side effects, and while they may slow the disease, they don’t cure it. Finally, studies have not proven that giving these therapies early in the course of the disease extends lives, the blog states.

Now, however, scientists are working on another option: a combination of the experimental immunotherapy SD-101 and low-dose radiation that, together, may slow the disease without serious side effects. Furthermore, their recent study of the regimen may help lay the groundwork for newer strategies capable of substantially reducing tumor size in a larger group of these patients.

The study’s results were published in August in the journal Cancer Discovery and discussed in a Cancer Currents article in September.

The findings of the small, phase 1/2 trial, in which the tumors of most patients shrank, are promising because the treatment pairing stimulated more and better responses than would be expected through rare events such as spontaneous remissions or the effects of local radiation reaching distant tumors, the researchers wrote. 

SD-101, in a drug class known as TLR9 agonists, contains a synthetic version of a substance the immune system releases when the body is infected by bacteria or viruses (cytidine–guanosine motifs, or CpG). The immune system recognizes CpG as an invader. When dendritic cells detect it, they mature and tell other immune cells that a threat is present. Those other immune cells then recognize and kill the cancer.

Radiating the tumors before injecting SD-101 helps to stimulate the immune system by destroying lymphoma cells and causing them to release proteins called antigens, the NCI explained. Dendritic cells activated by SD-101 can pick up these antigens and show them to other immune cells. In turn, those immune cells react by traveling through the bloodstream, hunting for those antigens and killing the lymphoma cells they sit on. This chain of events means that the therapy combination can shrink tumors throughout the body, not just in the location where SD-101 is injected, or where radiation takes place. The researchers refer to this dynamic as in situ vaccination.

The trial enrolled 29 previously untreated patients with slow-growing, low-grade B-cell lymphomas. Twenty-one of them had follicular lymphoma, four had marginal zone lymphoma, three had small or chronic lymphocytic lymphoma and one had cutaneous B-cell lymphoma. Each participant received 4 Gy of radiation to his or her largest tumor, and then an injection of SD-101 into the same tumor each week for five weeks. Doses of SD-101 varied.
In 26 participants, the injected tumor shrank, with one patient’s tumor disappearing. In 24 patients, tumors in other parts of the body also shrank; again, one patient had a complete response. About one-quarter of the participants experienced substantial shrinkage of their tumors. Tumor responses were durable, and could deepen over time, the researchers reported.

In patients whose tumors shrank, researchers found an increase of two types of immune cells that attack tumor cells, CD4 and CD8 effector T cells, and a decrease in cells that suppresses the immune system, known as T follicular helper and T regulatory cells. The researchers also noted that low pretreatment levels of several specific T cell types were associated with favorable outcomes. These included T regulatory cells that suppress the cancer-fighting proteins CD4 and CD8, and T cells that are equipped with CD8, but also carry a protein that inhibits it, granzyme B.

Side effects of SD-101 were flu-like, including chills, headache and fever, and lasted only a day or two. Those taking the highest dose, 8 mg, were the most likely to experience side effects, which included nausea and vomiting. Three patients delayed their treatment due to neutropenia (too few neutrophils in the blood, which increases susceptibility to infection) and one patient delayed due to pain at the treatment site. One patient stopped taking the treatment altogether because of fever and confusion, but those side effects dissipated quickly thereafter, the researchers reported.

The study’s senior investigator, Ronald Levy, M.D., professor and chief of the division of oncology at Stanford Medicine, in California, told Cancer Currents the results were exciting, but that more research needs to be done on the strategy.

The findings “were tantalizing, but not yet good enough,” he said. “We think we can do better by adding additional immune-stimulating agents to the platform that we've established here.”

A wide variety of immunotherapeutic and targeted drugs are being studied in combination with SD-101 or other CpG drugs, with or without radiation, to determine the best approach for these patients, the researchers noted.
 
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