Siddhartha Mukherjee, MD

Siddhartha Mukherjee, MD, assistant professor of medicine at Columbia University Medical Center, discusses potential means of targeting chimeric antigen receptor (CAR) T-cell therapy for patients with acute myeloid leukemia (AML).

There are currently few CAR T-cell therapies for AML based on available antigen targets that have shown efficacy. According to Mukherjee, his company Vor Biopharma is investigating CD33 and CLL-1 antigens, which are highly expressed in AML cells but are also expressed in healthy CD34+ human hematopoietic stem cells.

In order to improve targeting of CAR T-cell therapy, investigators are researching the impact of deleting these antigens from healthy hematopoietic stem cells through multiplex editing. The investigators have demonstrated with 

 models that gene-edited cells remain viable and persistent in the long term, so VCAR33-CLL1 multi-specific CAR T cells can be directed against AML cells without causing on-target, off-tumor cytopenic effects. Additionally, targeting multiple antigens could reduce the chance of tumor resistance.

Mukherjee says this is effectively bioengineering a unique tumor antigen. A trial of CAR T-cell therapy following this gene editing approach is now recruiting, and he hopes it will show efficacy and tolerability AML.

 In our trial, we delete an antigen from the donor cells, CD33 and maybe a couple of antigens we can delete, and then use the fact that now these normal cells don't have that antigen, while the AML cells have that antigen. We can now direct CAR T cells against AML cells. CD33 is 1 of them. There are 2 or 3 other antigens that we're working on. And all of a sudden now we’ve bioengineered a unique tumor cell antigen. That trial is also recruiting, and I think we're very excited about it. We, of course, don't have any data about it yet, but I'm optimistic that it will work.

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Siddhartha Mukherjee, MD, discusses potential means of targeting chimeric antigen receptor T-cell therapy for patients with acute myeloid leukemia.

Gene Editing Used to Enhance AML Antigen Targeting for CAR T-Cell Therapy

Siddhartha Mukherjee, MD, assistant professor of medicine at Columbia University Medical Center, explains the current golden standard for frontline treatment of patients with acute myeloid leukemia (AML).

Targeted therapies have allowed investigators to address the unique genetic makeup in select patients with AML. In recent years, clinical trials have evaluated chimeric antigen receptor (CAR) T-cell therapy approaches for the treatment of patients with this disease. With this, multiple agents have revealed promising results in a variety of hematologic malignancies, including within AML studies.

Currently, there are 2-3 targeted therapies available for genetic mutations, including 1 for patients who are positive for 

 mutations, and IDH inhibitors for patients that harbor mutations in the 

gene. Still, for patients with relapsed/refractory AML, enrollment in a clinical trial and allogeneic transplantation remain the core ways of treatment.

First, the thing to know about AML is that it's a very heterogeneous disease. The first thing we try to do is to subdivide patient populations based on their risk, if they're low-risk, intermediate-risk, or high-risk. These are defined by gene sequencing. Patients who are low-risk generally tend to respond better to chemotherapy. Patients who are intermediate-/high-risk generally tend to respond poorly to chemotherapy, and of course, those with high-risk disease respond extremely poorly to chemotherapy. Therefore, those low-risk patients are usually treated with chemotherapy upfront. High-risk patients are generally treated with a directionality towards allogeneic transplantation, and with intermediate-risk patients it's at the physician’s discretion.

There are 2 or 3 targeted therapies that are available for genetic mutations One of them would be for patients who are positive for 

mutations, and midostaurin [Rydapt] is 1 therapy available for them. Then, some patients have mutations in the 

 gene, and again, there are some IDH inhibitors available for them. That's been the standard of therapy for the frontline.

Siddhartha Mukherjee, MD, explains the current golden standard for frontline treatment of patients with acute myeloid leukemia.


Siddhartha Mukherjee, MD | Authors

Articles

Gene Editing Used to Enhance AML Antigen Targeting for CAR T-Cell Therapy

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