There is an urgent need for innovation in cancer treatments. Although we’ve seen significant progress in indications for drugs treating particular diseases, cancer research data shows that 10-year survival statistics for cancers such as esophageal and lung cancer, for instance, have shown only a 10 percent increase, while pancreatic cancer has shown no significant improvement since the 1970s. The implementation of targeted therapies in cancer treatment is an important step forward in improving the overall quality of life for patients fighting cancer. As researchers continue to learn more about specific changes in cancer cells, we’ll continue to see targeted therapies emerge; however, given the complicated nature of cancer, targeted therapies, such as antibody-drug conjugates (ADCs) will likely continue to be used in conjunction with other forms of treatment. ADCs are a relatively new class of anti-cancer agents that are highly targeted biopharmaceutical drugs. For the past 12 years, I’ve been incorporating ADCs into my clinical trials and have seen impressive results in treating the disease and feel there is still significant progress that can be made.

I initially started with monoclonal antibodies, also known as a “naked” monoclonal antibody. These worked great in some cancers, but had more modest effect in others. Researchers then combined this antibody with a payload (chemotherapy, radiation, or toxins), which ultimately provided impressively positive results. At this point, we began to explore how targeted treatments and usage of ADCs could essentially revolutionize how we approach treating cancer.

The evolution of ADCs as a new class of treatment 

ADCs combine monoclonal antibodies specific to surface antigens present on particular cancer cells with highly potent anti-cancer agents that are linked via a chemical linker. The agents can then deliver highly cytotoxic (anti-cancer) payloads directly to cancer cells. In some cancers, naked monoclonal antibodies work quite well, but in others, the success rate was less than ideal. Since then, we’ve been able to improve upon the distribution of treatment by delivering a payload with the antibody. For background, the antibody identifies something specific on cancer cells that we’re trying to target, and the payload delivers the therapeutics directly to that cancer cell in a more direct manner. In addition to chemotherapy payloads, there are also immunotoxins and radioimmunoconjugates that are all using the harnessing powers of antibodies to specifically target cancers.

Improving practices – the evolution ADCs

In clinical trials, the field of immunotherapy has been exploding; tailoring the treatment to the patient’s malignancies and leading to better treatments with less off-target effects than patients would experience with non-specific targeting. This non-specific targeting is what you’d experience with cytotoxic chemotherapies, which before targeted therapies had emerged, had been the traditional form of cancer treatment. There are several ADCs we’ve used within the hematology sphere, the first one was Mylotarg, which targeted CD33 cancer cells and had an anti-tubulin payload attached to it. The ADC that really opened doors in terms of hematologic malignancies was Brentuximab vedotin, an anti CD30 monoclonal antibody that has an anti-tubulin payload attached to it, MMAE. CD30 is an internalized-able self-surface marker that delivers chemotherapy directly into the cell, meaning that when the ADC binds to a CD30 expressing cell, it internalizes the whole molecule, including the payload, into the cell. The payload is then cleaved from the antibody and released intracellularly, meaning the chemotherapy is removed from the carrier and is distributed directly inside the cell. Whenever you’re giving cytotoxic chemotherapy into the vein, what you really want to know is the intracellular concentration in those cancer cells, and unfortunately, before you’d need a high serum plasma level of that drug to get the high levels needed to kill the cell (which meant giving high doses of drug in the vein). By using an antibody, you’re able to get the high levels into the cell without delivering high systemic concentrations of that chemotherapy, therefore decreasing toxicities, and improving efficacy.

The first study using Brentuximab vedotin to treat Hodgkin’s Lymphoma had positive outcomes, greatly improving progression-free survival. This ADC is also the first therapeutic that has been added to our chemoimmunotherapy in CD30 expressing peripheral T-cell lymphomas, which lead to the doubling of progression-free survival and improvement in overall survival. With this kind of response, it has become a wonderful drug to add to the treatment of CD30 positive cancers. So far, when we’ve incorporated ADCs into treatment during our clinical trials, the outcomes appear to be better, and results suggest it’s a valuable type of therapy. Since Brentuximab vedotin, other ADCs – such as trastuzumab deruxtecan and sacituzumab govitecan – have been used in the oncology space and have seen impressive outcomes.

There are also many impressive ADCs in development. I recently presented data at the European Hematology Association (EHA) conference using Naratuximab emtansine, an anti CD37 ADC. It was given with Rituximab (a naked anti CD20 antibody) in a heavily treated group of relapsed/refractory large B cell lymphoma. It demonstrated a good efficacy/safety profile, with high response rates, including many deep and durable responses. Furthermore, very few patients discontinued due to treatment-related adverse events. Given these characteristics, this therapy may prove quite useful in our treatment of this aggressive lymphoma.

What does this mean for the patients? 

There are a variety of ongoing clinical trials, and in an attempt to achieve different and better results, we prefer to try a treatment regime that is targeted rather than something the patient has either tried before or could potentially have negative impacts on other parts of the body. For example, chemotherapy has a proven track record of targeting and killing cancer cells, but it also significantly impacts healthy cells throughout the body, making it extremely taxing on the patient and not an effective long-term solution in treating the disease. However, using anti-tubulin agents alone isn’t an effective treatment regime either, but when we’re able to get the highly concentrated payload linked to the antibody and directly release it to the target and/or tumor, they become a highly effective form of treatment resulting in the destruction of the cancer cell itself. Ideally, we’re able to do this in a way that is tolerable for the patient, leading to less neuropathy and gastrointestinal toxicities than they would experience with a non-targeted treatment approach and ultimately less disruption to everyday life.

Moving forward: Where do we go from here? 

Developing an ADC is not an easy feat. Due to their complex nature, it is challenging to produce ADCs. There are three parts to an ADC and all of them are essential for the ADC to be effective: the antibody – which is the protein component that specifies a target, the payload (the cytotoxic drug), and the linker. The linker attaches or “links” the payload to the antibody in order to deliver the payload directly to the cancerous cell. Complexities associated with developing effective ADCs for treatment are ensuring that it doesn’t dissociate before reaching its target, as well as ensuring the molecules are properly labeled. For companies without experience, this can be challenging. For example, when we talk about the first ADC that was available in hematology, which was the Mylotarg, it was more of a primitive linker where only half of the molecules were labeled. Now, if you look at subsequent CD30 ADCs, they had 100 percent of the molecules labeled and a better linker, so it had less disassociation before it reached its target, ultimately improving the overall results of the treatment. There’s a lot of engineering and planning that is involved in developing an effective and well-targeted ADC. It’s tough to say what the future will hold for the future of these antibodies. ADCs are rather larger in size and there may be other ways we can deliver targeted therapies without using the whole antibody. It’s not going to be the answer for everything, but it’s moving the needle forward in terms of improving patient outcomes in clinical trials, without having to compromise healthy cells, which can ultimately improve quality of life.

M. Yair Levy is a hematologist-oncologist.

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