Inotuzumab and MRD Understanding the Importance of Targeted Therapy in Cancer Treatment

Inotuzumab and MRD Understanding the Importance of Targeted Therapy in Cancer Treatment

Summarized from Van Huynh, MD’s video on MRD: 2023 ASH ALL Inotuzumab Update [Slides] – MOASC

Hematological malignancies like acute lymphoblastic leukaemia (AML) are diseases that affects millions of people worldwide, and it is essential to have effective treatments that can target the specific type of cancer and its underlying genetic mutations. Targeted therapy is a type of cancer treatment that aims to inhibit the specific genetic mutations or proteins that drive the growth of cancer cells. In this article, we will explore the concept of targeted therapy and its role in treating cancer.

How Does Targeted Therapy Work for Patients With Minimal Residual Disease (MRD)?

Targeted therapy works by targeting specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. Unlike traditional chemotherapy, which targets rapidly dividing cells and can harm healthy cells, targeted therapy is designed to specifically attack cancer cells while sparing normal cells.

There are several types of targeted therapies, including small molecule inhibitors, monoclonal antibodies, and cytokine therapy. Small molecule inhibitors are drugs that can penetrate cancer cells and directly inhibit specific proteins involved in cancer growth and progression (antibody drug conjugates). Monoclonal antibodies are laboratory-made molecules that mimic the immune system’s ability to fight off harmful substances in the body. Cytokine therapy is a type of immunotherapy that uses natural substances called cytokines to enhance the body’s immune response to cancer.

What is Inotuzumab Ozogamicin?

Inotuzumab ozogamicin is not a tyrosine kinase inhibitor it is an antibody-drug conjugate utilizing linker and cytotoxic drug technology similar to that developed for the ground-breaking treatment Mylotarg (Gemtuzumab ozogamicin), which was approved by the US Food and Drug Administration in 2000 for the treatment of acute myeloid leukemia. Inotuzumab ozogamicin comprises of a recombinant humanized IgG4 kappa CD22-targeting monoclonal antibody covalently linked to a potent DNA-binding cytotoxic agent 4, N-acetyl-gamma-calicheamicin dimethylhydrazide. EU approved inotuzumab ozogamicin in June 2017, followed by FDA by the United States Government on August 17, 2017, for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The drug was developed by Pfizer and UCB (ALL). Acute lymphoblastic leukemia (ALL) is a fast growing malignancy of the bone marrow linked with high mortality rates and poor response to traditional chemotherapies in relapsing cases. In a randomized trial, inotuzumab ozogamicin was associated with a greater proportion of patients experiencing longer periods of full remission without evidence of disease than other therapies.

Inotuzumab ozogamicin consists of the cytotoxic antibiotic N-acetyl-gamma-calicheamicin dimethylhydrazide linked to a humanized monoclonal IgG4 antibody via a 4-(4 acetylphenoxy) butanoic acid (acetyl butyrate) linker. When the antibody binds to the CD22 receptor on the surface of B cells, the medication produces a powerful cytotoxic impact against CD22+ B-cell lymphoma. The drug-CD22 complex is rapidly absorbed into the cell, resulting in the formation of an endosome that merges with lysosomes. The intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide into the acidic environment. N-acetyl-gamma-calicheamicin dimethylhydrazide is a calicheamicin derivative that is produced naturally by Micromonospora echinospora and is hazardous to the body when not bound to an antibody. It mediates cell death by binding sequence-specifically to the minor groove of DNA and undergoing a structural change to create diradicals 6. These modifications remove hydrogen ions from the phosphodiester bonds of double-stranded DNA, causing breakage and apoptosis.

Advantages of Targeted Therapy For Patients with Acute Lymphoblastic Leukemia

Targeted therapy offers several advantages over traditional chemotherapy, including:

• Higher effectiveness: Targeted therapy is more effective in treating specific types of cancer, such as melanoma, lung cancer, and some forms of leukemia, by directly inhibiting the specific genetic mutations that drive the growth of cancer cells.

• Fewer adverse effects: Targeted therapy is less toxic with no serious adverse event to normal cells, resulting in fewer side effects compared to traditional chemotherapy.

• Improved quality of life: Targeted therapy allows patients to continue with their daily activities and maintain a better quality of life during treatment.

• Long-lasting benefits: In some cases, targeted therapy can lead to long-lasting remissions and in some cases complete remission.

Examples of Targeted Therapies

There are several clinical trial that have been FDA-approved targeted therapies for different types of cancer, including:

• Herceptin (trastuzumab) for HER2-positive breast cancer

• Gleevec (imatinib) for chronic myeloid leukemia and gastrointestinal stromal tumors

• Avastin (bevacizumab) for several types of cancer, including colon, lung, and kidney cancer

• Opdivo (nivolumab) for melanoma, non-small cell lung cancer, and kidney cancer

• Besponsa (inotuzumab ozogamicin) for acute lymphoblastic leukemia

Conclusion

Targeted therapy like inotuzumab ozogamicin has revolutionized the treatment of cancer and offers a more personalized approach to treating the disease. By targeting specific genetic mutations or proteins, targeted therapy can effectively inhibit the growth of cancer cells while minimizing harm to normal cells. You don’t need a central line for this type of treatment. If you or a loved one has been diagnosed with cancer, it is essential to discuss all available treatment options, including targeted therapy, with your healthcare provider.

Van Huynh, MD – About The Author, Credentials, and Affiliations

Van Huynh, MD, is a CHOC Children’s Oncology specialist. She holds board certifications in both pediatrics and pediatric hematology-oncology. Her clinical interests include acute lymphoblastic leukemia (ALL) in children, leukemia relapse, immunotherapy, and bone marrow transplantation.

Dr. Huynh attended the UC Irvine College of Medicine in California for medical school. She did her residency in pediatrics at Harbor-UCLA Medical Center, and then she did her fellowship in pediatric hematology-oncology at CHOC Children’s Hospital. She is the primary investigator (PI) for CHOC’s Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium, a multi-center collaboration that provides novel therapeutic choices for patients with relapsed or resistant leukemia and lymphoma. Dr. Huynh manages the CAR T cell program at CHOC Children’s and is the PI for the ZUMA-4 CAR T-cell Trial.

Reference

1. DrugBank Online – Inotuzumab ozogamicin. DrugBank Online, June 3, 2022

2. National Cancer Institute – FDA Approves Inotuzumab for Adults with B-Cell Acute Lymphoblastic Leukemia. National Cancer Institute, September 18, 2017