Multitargeted Therapeutics Make Headway in Hematologic Malignancies

David S. Hong, MD,

David S. Hong, MD

Multitargeted therapies may be more efficacious and safer compared with using combination regimens or even single-agent therapies by targeting more than 1 target with only 1 drug. At the 2019 SITC Annual Meeting, a panel of experts discussed the development of multitargeted therapeutics and addressed the evolution of these agents in hematologic malignancies.

When using 2 more drugs, sequencing the drugs can become a challenge and they may not interactionwell. The cost of administering 2 drugs could be significantly higher than using 1 agent alone, as well. Combining 2 constructs in 1 molecule could also help in overcoming tumor heterogeneity.

These agents have been tested in hematologic malignancies and have provided hope as a treatment option. Efficacy appears high with these therapies in hematology. However, multitargeted therapies are still in the early stages of development for patients with solid tumors. Investigators are evaluated how these agents could also be used in this patient population to help overcome challenges with the tumor microenvironment.

“Everyone is excited about the fact that these are new therapies and that they have the opportunity to help overcome mechanisms of resistance, mechanisms of tumor heterogeneity, and perhaps just overall be more efficacious than even single-agent or combination immunotherapy regimens that have been in clinical trials for the last several years,” David S. Hong, MD, said.

In an interview withTargeted Oncology, Hong, deputy director of the Department of investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the emerging role of multitargeted therapeutics in patients with hematologic malignancies. He highlights the FDA’s approval of blinatumomab, a bispecific T-cell engager (BiTE), for the treatment of patients with acute lymphocytic leukemia (ALL).

TARGETED ONCOLOGY: What did the panel discussion highlight at the meeting?

Hong:It was a very interesting panel discussion on the different emerging and existing platforms of multitargeted therapy. When we talk about multitargeted therapy, we are talking about a number of different constructs, primarily antibodies or antibody-like constructs that can target 2 different targets. Usually, in this case, it is something like a CD3 on a T cell and some antigen on a tumor-specific antigen.

What was also very interesting was the discussion on how CAR T cells can be engineered to be multitargeted platforms in this context. The session discussed a wide variety of variations of different multitargeted platforms that are emerging in the immunotherapy drug development space. We discussed some of the challenges and also some of the benefits as well as disadvantages of the different platforms.

TARGETED ONCOLOGY: What types of therapies are considered multitargeted?

Hong:In most cases, we are talking about antibody platforms, such as BiTEs or bispecific antibodies. Again, these are antibody constructs that are engineered to target 2 different entities, such as 2 different antigens, receptors, or different types of cells in order to induce cancer tumor cell kill.

TARGETED ONCOLOGY: What are the benefits of implementing this strategy?

Hong:There are a lot of advantages. Oftentimes, 2 drugs are not always better than 1 for a number of logistical reasons. Giving 2 drugs can be complicated in scheduling and how things can interfere with each other. The idea of putting 2 different antibodies in 1 construct can lead to better structural efficacy and perhaps even more efficacy in a way that perhaps 2 antibodies cannot.

Two constructs, which came up in the panel, can also overcome tumor heterogeneity. From a practical cost perspective, you could argue that if you have 2 antibodies, the cost of multiple biologic therapies could be significant relative to 1 that could probably do the same concept in 1 molecule.

TARGETED ONCOLOGY: How have these therapies improved the care of patients with cancer?

Hong:The only drug approved now is a bispecific called blinatumomab. That is what is called BiTE. That drug is approved in ALL and has benefited several other indications outside of ALL. It has shown benefit in patients with chemotherapy-refractory ALL. There is hope that other multi-platforms can affect other tumor types beyond hematologic malignancies, perhaps in solid tumors and other types of cancers as well.

TARGETED ONCOLOGY: What are the ongoing challenges with the development of these therapeutics?

Hong:The unmet need is huge. We still haven’t cured metastatic cancer, and there are many cancers do not have effective therapies. I think the hope is that some of these multitargeted platforms will, at least immunotherapy-wise, help overcome tumor heterogeneity, help overcome the tumor microenvironment challenges that we see with solid tumors and epithelial tumors, and also show high efficacy in hematologic malignancies.

The reason we still spend so much money in drug development in cancer is because despite the many new and transforming drugs that have emerged, there is still an incredible need to help our patients who are suffering from cancer.

TARGETED ONCOLOGY: Were there any areas of contention among you and the other panelists?

Hong:There wasn’t a whole lot of contention in that panel. I think everybody agreed with many of the same points. Many panelists were representatives from companies that were testing novel multitargeted platforms, some in the antibody/antibody-like space and those in the cellular or CAR T space. That was the biggest difference, and some people in the CAR T space would argue that area has the potential of perhaps reducing significant remission and perhaps even cure in those cases.

There was a lot of discussion about the pros and cons of both therapies, particularly such as in the context of the multitargeted platforms. One big question that emerges is immunogenicity. How do we prepare for that in the context of drug development? Relative to something like CAR T, I don’t think there has been a lot of concerns about immunogenicity, but those were some of the discussion points that emerged.

Everyone is excited about the fact that these are new therapies and that they have the opportunity to help overcome mechanisms of resistance, mechanisms of tumor heterogeneity, and perhaps just overall be more efficacious than even single-agent or combination immunotherapy regimens that have been in clinical trials for the last several years. I think everybody is excited about how that may play out.

TARGETED ONCOLOGY: Which hematologic malignancies have responded best to this approach?

Hong:To date, blinatumomab has been the poster child of these multitargeted platforms. I think we are all hoping that beyond ALL, other hematologic malignancies, such as acute myeloidleukemiaor DLBCL, will receive benefit. There are suggestions that other platforms are working in hematologic malignancies as well.