"The goal is to understand better why certain patients respond well to some therapies and others do not, and then simultaneously try to identify ways to overcome treatment resistance or get better responses to treatment," says Dr. Robert Kridel, a staff physician and clinician scientist at Princess Margaret Cancer Centre. (Photo: UHN)

September is World Leukemia and Lymphoma Awareness Month. Dr. Robert Kridel, a staff physician and clinician scientist at Princess Margaret Cancer Centre, sat down to talk about blood cancer lymphoma and his research, which focuses on improving lymphoma diagnosis and treatment to be better tailored to individual patients.

Q: What is lymphoma and why do we need to care about it?

(Dr. Kridel) Lymphoma is a type of blood cancer that affects cells of the lymphatic system. It is a common disorder, with about 12,000 Canadians diagnosed every year. While many lymphomas are treatable, patients often suffer toxicity from chemotherapy. There are also many lymphomas that are not curable, and aggressive lymphomas are often resistant to treatments at the time of relapse. These patients usually don't benefit so much from chemotherapy and have a risk of dying from the disease.

Q: What are different types of lymphoma and what is the current standard of care?

There are many different types of lymphoma, each with their own characteristics and treatment options. The main categories are Hodgkin and non-Hodgkin lymphoma, with the vast majority being the latter. Within this type, there are B-cell and T-cell lymphomas. B-cell lymphomas are more common and include diffuse large B-cell lymphoma (DLBCL), the most common and an aggressive form of lymphoma, and follicular lymphoma (FL), the most common indolent lymphoma. The standard treatment for DLBCL is multi-agent chemotherapy, which can cure about 60 per cent to 70 per cent of patients. However, some patients do not respond to this treatment or have a relapse of the disease. The standard treatment of FL is also chemotherapy, followed by most patients achieving long remissions, while some experiencing early relapse.

Q: Can you speak more to the problem of disease relapse in treating lymphoma and the effort to address this issue?

Many who have gone through first-line and sometimes second-line treatment can still experience relapse and need further treatment. However, the options thereafter are not very well defined. We are currently studying how to improve the treatment for lymphoma patients who are resistant to the standard therapy. Our lab explores if personalized medications that are less toxic than chemotherapy can be a third-line treatment option.

A third-line drug that is currently under clinical investigation–called EZH2 inhibitor – has caught our attention. Based on a reported study, the patients can have a response that lasts about a year with no major side effects. The medication works by targeting EZH2, a protein whose gene is mutated in about 20 per cent to 25 per cent of FL cases.

However, resistance is also present for this new drug candidate. Not all patients can benefit from it, even if their lymphoma has the mutation in the gene. Our research aims to improve patient responses to EZH2 inhibitors and identify biomarkers for predicting response.

Q: What is the overarching goal and major approach behind your lymphoma research?

The goal is to understand better why certain patients respond well to some therapies and others do not, and then simultaneously try to identify ways to overcome treatment resistance or get better responses to treatment. I think there's an opportunity to combine multiple non-toxic targeted treatments to achieve a better efficacy. Combined therapy is already used for treating some infectious diseases such as tuberculosis or HIV. Chemotherapy also combines different medications together. They leverage the strengths of different drugs to achieve a more desired result. For targeted therapies, there is also an opportunity to learn how to combine treatments to make them better.

Q: What is the main consideration when designing a combined therapy?

Different investigators may choose different drug combinations in clinical trials. Then the trial number can be endless if there is no justification for the combinations. This is specifically what we try NOT to do. We want to be rational in the way of how we decide the best combination therapies.

Q: Can you give us an example of designing a combined therapy that is rational?

We selected a medication in combination with EZH2 inhibitor to improve the drug's response, based on cancer cell genetic profile and their sensitivity to different drugs.

The technique we applied is called CRISPR-Cas9 technology, which allows us to precisely modify a gene, leading to a protein that is no longer being produced. Then these modified type of cancer cells were treated with the EZH2 inhibitor. The goal was to identify a specific gene that, when it was modified, the cells became more sensitized to the effect of the inhibitor, meaning that the loss of this gene enhanced the drug response. Instead of testing one gene at a time, the lab conducted the experiments at scale where one screening examined all genes at once.

The top candidate gene that came out of the screening was called IKZF1, which encodes a protein called IKAROS, that can also be targeted by a drug called lenalidomide. Lenalidomide is an immunomodulatory drug that has been used in other blood cancers, such as multiple myeloma. It works by degrading certain proteins in the cells, including IKAROS, which is involved in the survival and growth of lymphoma cells.

So what we were able to show is that combining lenalidomide with an EZH2 inhibitor, can produce synergistic effects and kill more cancer cells in a preclinical model. This is a promising finding that could lead to better outcomes for lymphoma patients whose lymphoma is resistant to other treatments. We eventually published our finding in Clinical Cancer Research in 2021.

Q: What are other areas of research that might help lymphoma treatment more personalized? What is the outlook for treating lymphoma?

Besides tackling treatment resistance, the progress towards personalized medicine also involves improving the classification and diagnosis of lymphoma. As patient trajectories can be very different despite the similarity in the initial diagnosis and pathology, our research also looks into identifying subtypes of lymphoma to understand the differences between groups of patients and their responses. Another critical project involves exploring the use of liquid biopsies for lymphoma diagnosis and as biomarkers to track treatment response more effectively.

With recent research and treatment advances, survival rates for those who are diagnosed with non-Hodgkin lymphoma have greatly improved during the last 30 years. And for Hodgkin lymphoma, more than 80 per cent of cases can be cured with standard chemotherapy, radiation therapy, or both. While there are undoubtedly areas that require further advancement, it's important to acknowledge that the future is far from bleak.

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