Frontline CD30 ADC for Advanced Classical Hodgkin Lymphoma - Episode 2

Targeting CD30 in Classical Hodgkin Lymphoma

Siddhartha Ganguly, MD, FACP:We have heard about CD30. CD30 is membrane-related and Golgi perinuclear-related antigen that identifies Reed-Sternberg cell in a patient with Hodgkin lymphoma. The CD30 antigen is a receptor of tumor necrosis factor, or TNF superfamily. And once the CD30 is activated, it sends a signal inside those cancer cells and they upregulate some of the positive pathways that eventually culminate into NF-κB, which will translocate into the nucleus leading to growth, development, and nurturing of the cancer cells in the milieu of multiple other inflammatory cells in a classic Hodgkin lymphoma, lymph nodal tissue.

This actually seems like the CD30 and the CD ligand are necessary for the survival of the Hodgkin lymphoma cells. Can you, Dr Galal, tell us a little more about the CD30, whether it’s expressed in all Hodgkin lymphoma cells and why it is so important, the diagnosis, and whether CD30 is expressed in any other cells in our human body.

Ahmed Galal, MD, FRACP, MSc:CD30 is a very important receptor that goes through a pathway in the cell, intracellularly, that affects their apoptotic process that makes actually, under normal circumstances, goes through the NF-κB and other pathways that will lead to the enhancement or prevention of the apoptosis or enhancement of cell survival. Blocking this kind of receptor might affect the cell survivor and kill these cells because they are tumor cells.

Siddhartha Ganguly, MD, FACP:CD30 is expressed in almost all Reed-Sternberg cells in patients with Hodgkin lymphoma. It is not only important for diagnosis but also our target for the topic of today’s discussion: precision medicine. It is an excellent example of targeted drug-delivery system.

CD30 monoclonal antibodies, when first used in Hodgkin lymphoma, just a naked antibody, did not really show us much response. But brentuximab vedotin is a paradigm-changing antibody drug conjugate. What that means is that the anti-CD30 monoclonal antibody has a linker. And with this linker, our toxin is attached. And the name of the toxin is MMAE [monomethyl auristatin E]. It’s very interesting. This toxin was originally extracted from a sea animal called sea hare. I didn’t know such an animal existed until I looked it up. It looks like a blob on the ocean floor. And this toxin is very potent.

What happens when this antibody drug conjugate, carrying that toxin, is given to a patient with Hodgkin lymphoma is that this antibody will target the CD30-positive cancer cells. And on the surface of the cancer cells that carries the CD30, this entire antibody drug conjugate will be internalized, the linker will dissociate inside those cancer cells, and then the MMAE is a very potent toxin that breaks down the tubulin structure of the cancer cells. And if you remember your biology 101, the tubulin is very important in making mitotic spindles, cell division, and growth, and thereby, by breaking that internal structure, the cancer cells die of an apoptotic programmed cell death. This is a fantastic way of a targeted precision medicine drug-delivery systems, like a payload reaching only for those CD30-positive cells.

Dr Galal, how does brentuximab vedotin differ from other antibodies like rituximab or intracellular molecules like everolimus, that I hear we are using in patients with Hodgkin disease?

Ahmed Galal, MD, FRACP, MSc:When you look at other targeted therapies like rituximab and the other monoclonal antibodies, these are naked antibodies that go directly to the receptor. The brentuximab vedotin has the advantage of chemo-conjugated kind of antibody that, once it hooks to the receptor, can internalize the chemotherapeutic agent, which is the monomethyl auristatin E, a microtubule disruptive agent that will lead to cell death. Also, having an antibody on the surface of the cell that might mediate the cell-mediated dependent or cell-dependent death of these cells by the macrophages and other immune system mechanisms. That might lead to lysis of the cell with a different mechanism. When the cell ruptures, the residual of the MMAE might lead to killing of the other tumor cells around it in the tumor environment.

The advantage of having brentuximab vedotin is that it’s a different mechanism of action that leads to tumor cell killing effectively. You have the chemotherapy agent that’s directed to these cells, and you have the immunological part of the process itself that will lead to very effective treatment. And in combination with other chemotherapy, we’ve seen so much advantage in different diseases like the Hodgkin lymphoma, the peripheral T-cell lymphoma, and other B-cell lymphomas that would have CD30 positivity. It’s adding to the effect of chemotherapy that’s traditionally used in this kind of disease and killing of these tumor cells.

The preclinical data in the animal model showed effectiveness of the naked antibody, and then the naked antibody was used in different CD30-positive lymphomas. However, it didn’t prove to be really effective, so the progression of that went to the immunoconjugates and also the radio conjugates and then ended up with the brentuximab vedotin with a chemotherapeutic agent on top of it, which works very effectively. The first phase I trials in the clinical arena were in the CD30-positive different hematologic malignancies in the relapsed and refractory stage that showed efficacy. Then after that, it was introduced to post-transplant, sort of consolidation for patients who have high risk of relapse. And now it has been used more and more in the relapsed-refractory and the frontline therapy as we discussed in classical Hodgkin and T-cell lymphoma.

The CD30 positivity is based on the immunohistochemical or flow cytometry testing that would define the CD30. Initially, we were getting reports from pathology by positive or negative, but recently we’re getting percentages, which is much better. In the clinical trials, many of the studies used 10% as a cutoff, but really there is no clear standard. For instance, in cutaneous T-cell lymphoma, when we have CD30 positivity even at a very low level, we see very good responses for brentuximab vedotin as a single agent. I think that positivity and negativity and the percentage are valid. However, there is no clear cutoff of the positivity there.

Transcript edited for clarity.