Leading expert in pediatric oncology and leukemia genomics, Dr. Shai Izraeli, MD, explains how immunotherapy and precision medicine are revolutionizing the treatment of relapsed childhood leukemia. He details the critical importance of fresh genomic sequencing at relapse to identify new mutations and genomic instability, which can be targeted with novel therapies like immune checkpoint inhibitors to overcome treatment resistance and improve patient outcomes.
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Immunotherapy and Genomic Sequencing for Relapsed Childhood Leukemia
Jump To Section
- Leukemia Relapse Challenge
- Genomic Markers for Prognosis
- Mechanisms of Treatment Resistance
- Genomic Instability and Immunotherapy
- Precision Medicine and Fresh Sequencing
- Future of Leukemia Therapy
Leukemia Relapse Challenge
Recurring or relapsed leukemia presents a major treatment challenge in pediatric oncology. Dr. Shai Izraeli, MD, a leading expert, emphasizes that genetic alterations in cancer cells are key to understanding this challenge and unlocking new immunotherapy options. The genomic landscape of the disease evolves, making relapse a complex clinical scenario that requires a sophisticated diagnostic approach.
Genomic Markers for Prognosis
Research into the genomics of leukemia progression has identified specific genomic markers that serve as powerful prognostic factors at initial diagnosis. Dr. Shai Izraeli, MD, explains that these markers help stratify leukemia treatment intensity. Using molecular markers allows oncologists to potentially reduce the intensity of therapy for some patients, thereby lowering the risk of long-term side effects and toxicity from cancer treatment, a crucial consideration for children.
Mechanisms of Treatment Resistance
Leukemia relapse is a complex process driven by several mechanisms. A primary cause is the selection of mutations that confer resistance to the cancer medications used in initial therapy. Dr. Shai Izraeli, MD, provides a specific example from his work on leukemia in patients with Down syndrome. While a specific medication may be effective initially, relapse is often caused by the outgrowth of a resistant clone of cancer cells, a phenomenon he describes as a "molecular escape." This necessitates finding entirely new therapeutic pathways.
Genomic Instability and Immunotherapy
A significant and encouraging finding is that up to 15% of relapsed leukemia cells exhibit high genomic instability, specifically a mismatch repair deficiency. Dr. Shai Izraeli, MD, notes that this is a valuable target in the age of precision medicine. Genomically unstable cancer cells are more recognizable to the immune system but are often able to evade it. Immune checkpoint inhibitors, a Nobel Prize-winning class of drugs, can reinvigorate the immune system to attack these foreign cells, offering a potent new therapy option for this subset of relapsed leukemias.
Precision Medicine and Fresh Sequencing
Dr. Shai Izraeli, MD, stresses that it is not wise to rely solely on mutation data from the primary tumor. The genetic profile of cancer shifts over time due to the selective evolutionary pressure of treatment. For any metastatic or relapsed cancer, fresh genomic sequencing is absolutely crucial. This is the cornerstone of precision medicine, where therapy is targeted to the specific genetic mutation or chromosome abnormality present at the time of relapse, which may be entirely different from the initial diagnosis.
Future of Leukemia Therapy
The future of treating relapsed childhood leukemia lies in adaptive, genetically-informed strategies. The insights from Dr. Shai Izraeli, MD, highlight that a one-time biopsy is insufficient. Continuous genomic monitoring and a deep understanding of mechanisms like molecular escape and genomic instability are paving the way for more effective, less toxic immunotherapies. This approach moves beyond a one-size-fits-all model to a dynamic, personalized treatment plan that evolves with the disease.
Full Transcript
Dr. Anton Titov, MD: Recurring or relapsed leukemia is a major treatment challenge. A leading pediatric cancer expert explains how genetic alterations in cancer cells help to use immunotherapy for leukemia treatment.
Why must fresh genomic sequencing of relapsed leukemia cells be done? Any metastatic cancer must be sequenced. It is not wise to rely only on mutations discovered in the primary tumor.
You also study the genomics of leukemia progression in children. You identified some of the genomic markers of leukemia that could serve as prognostic factors at the time of leukemia diagnosis.
Dr. Shai Izraeli, MD: That helps, obviously, to stratify leukemia treatment. As you mentioned before, using molecular cancer markers can help to reduce the intensity of leukemia treatment. The goal is to lower the potential side effects and toxicity of cancer therapy in the long term.
Relapse of leukemia is very tricky. We found a couple of mechanisms for relapse of leukemia.
Dr. Anton Titov, MD: One of them is the selection of mutations that provide resistance to cancer medications that we use. For example, I mentioned the discovery that we made in leukemia in patients with Down syndrome. This leukemia may be treated by a specific cancer medication.
Dr. Shai Izraeli, MD: But we found that the leukemia relapse is often caused by the cancer cells that are resistant to this cancer medication. We need to find another way to treat relapsed leukemia.
Dr. Anton Titov, MD: A molecular escape of child leukemia.
Dr. Shai Izraeli, MD: A molecular escape, exactly! We identified several encouraging factors to treat child leukemia relapse. Up to 15% of leukemia cells at leukemia relapse are very genomically unstable.
Dr. Anton Titov, MD: Why is this a potentially good finding?
Dr. Shai Izraeli, MD: Because genetic instability of a tumor is valuable information in the age of precision medicine. In precision medicine, we don't talk about a cancer medication that is specific to a disease. We use cancer medication that is specific to a genetic mutation or chromosome abnormality.
For example, we found cancer medications that are called immune checkpoint inhibitors. When I say "we," I mean the pediatric leukemia scientific and medical community. The Nobel Prize was given this year for these cancer medications.
Immune checkpoint inhibitors are effective especially for genomically unstable cancer cells.
Dr. Anton Titov, MD: Why?
Dr. Shai Izraeli, MD: Because genomically unstable cancer cells are recognized. But the normal immune system is weak. If you give cancer medications to encourage the normal immune system, they will attack these foreign cancer cells.
We found several leukemia therapy options in this clinical trial that you mentioned. About 15% of all leukemic cells have this genomic instability phenotype. We call it mismatch repair genomic instability.
Immune checkpoint inhibitors may be effective for some relapsed leukemias. It's also very important to study the genomics of relapsed leukemia. In childhood cancer in general, or in any cancer in general, it is crucial information.
Because the same abnormalities that existed in the beginning of cancer may not be present at the time of the cancer relapse. You have to think about targeted cancer therapy. We do need to know what is the genetic abnormality in the relapsed cancer.
Because the genetics of the tumor shifts with time. There is a selective evolutionary pressure from the treatment.
Dr. Anton Titov, MD: The genetic profile of the metastatic lesions changes from genetic mutations in the primary tumor.
Dr. Shai Izraeli, MD: Precisely!