Debu Tripathy, M.D.

 Magazine touches upon the use of antibody-drug conjugates in managing breast cancer.

In this winter issue of CURE, we review the rapid expansion in the current use and development of antibody-drug conjugates (ADCs), a class of drugs with a long history, but a more recent accelerated rate of approvals, with many new versions queued up in the pipeline.

The first ADC approved by the Food and Drug Administration (FDA) was Mylotarg (gemtuzumab ozogamicin) for use in refractory acute myeloid leukemia (AML), which targets the protein CD33 expressed on AML cells, in 2000. However, there was still a rocky road ahead — the drug was later withdrawn from the market due to significant side effects on the liver and potentially fatal allergic reactions. It was reapproved for newly diagnosed CD33-positive AML at a lower dose in combination with chemotherapy with strict monitoring guidelines in 2017. To date, 13 ADCs have been approved across numerous cancer types.

Several innovations to ADCs have occurred over the years, making these drugs even more effective and better tolerated. For one, we now have extensive information about proteins expressed uniquely on cancer cells. This helps drug and biotech companies to better focus their development and for patients to be rapidly screened in situations where the protein is not always present on the tumor.

Additionally, the antibodies used can themselves have therapeutic effects and properties that allow them to more efficiently be “endocytosed” or taken in by the tumor cells. The payload can be drugs that are too powerful to be used as “naked” drugs, but safe enough when used in an ADC where exposure is more controlled. Drugs not typically used in earlier lines of treatment can be incorporated into ADCs, lowering the chance of preexisting drug resistance.

The drug-to-antibody ratio can also be made higher to deliver more drug to the tumor. The linker that is broken to release the drug into the cell can also be synthesized in a form to be broken based on the pH (acid content) inside the cell and other characteristics to optimize its impact. Even newer features are being developed such as using targeted drugs as the payload instead of chemotherapy, such as small molecules that are immune-stimulating or that block growth factor, cell cycle and other oncogenic (cancer-driving) pathways.

Many experts predict ADC use will expand and become more personalized based on cancer type and specific proteins expressed by the cancer as well as previous treatments the patient has received. The lower toxicities may allow the drugs to be used to prevent recurrences (or in the adjuvant setting), as is the case for Kadcyla (ado-trastuzumab emtansine, T-DM1), approved for HER2-positive breast cancer when there is residual invasive cancer seen at surgery following preoperative chemotherapy plus HER2 antibody treatment. Next-generation sequencing of tumor DNA and RNA coupled with artificial intelligence-powered analyses may help point to appropriate ADC therapy for specific cases, further individualizing cancer treatment in the near future.

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Articles

Antibody-drug conjugates (ADCs) have seen rapid development and increased FDA approvals, with 13 currently approved for various cancers. Innovations have enhanced ADC efficacy and tolerability, including better targeting of cancer-specific proteins, improved antibody properties, and optimized drug delivery mechanisms. These advancements allow for more personalized cancer treatment, potentially reducing toxicities and preventing recurrences. Future developments may involve next-generation sequencing and AI to further tailor ADC therapies. The evolution of ADCs signifies a promising shift towards more individualized and effective cancer treatment strategies.

Since 2000, antibody-drug conjugates have been approved by the Food and Drug Administration for various cancer types, such as breast cancer. 

The ABCs of ADCs in Breast Cancer

Dr. Debu Tripathy, Professor of Medicine Chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center.

An innovative and groundbreaking cancer treatment has been made available earlier to patients with multiple myeloma, as chimeric antigen receptor (CAR)-T cell therapy is propelled ever closer to the front line of treatment.

In this special issue of CURE, we spotlight the use of CAR-T cell therapy in recent years to treat multiple myeloma, a cancer of the plasma cells — a type of immune cell that produces antibodies. CAR-T cell therapy involves extracting, modifying and reinfusing a patient’s own T cells, a type of immune cell, to specifically recognize and attack cancer cells.

“Cancers of the immune system often know all the tricks of the immune system and are able to bypass them,” Dr. Rahul Banerjee, assistant professor in the division of hematology and oncology at the University of Washington and assistant professor in the clinical research division at the Fred Hutch Cancer Center, both in Seattle, told CURE. “With CAR-T, you level the playing field.”

The first Food and Drug Administration (FDA) approval of a CAR-T cell therapy to treat multiple myeloma, Abecma (idecabtagene vicleucel),came in 2021, followed by Carvykti (ciltacabtagene autoleucel) in 2022. Both were approved for patients who had received at least four prior lines of treatment, but earlier this year, the FDA approved Abecma for patients who had received two prior lines of therapy and Carvykti for patients who had received one prior line of treatment. Successful treatments are often eventually tested at earlier stages of therapy, although

safety and toxicities are important factors in sorting out the optimal sequence of deployment.

We spoke with experts about current clinical trials evaluating CAR-T cell therapy in even earlier lines of therapy as well as developments in treatment strategies. We also discuss the challenges,

side effects and potential of these treatments as they currently exist.

“I would say [for] CAR-T cells in general, not just for myeloma but for all cancers, we’re in the same place as we were for stem cell transplantation back in the ’70s and early ’80s,” Dr. Saad Usmani, chief of myeloma service at Memorial Sloan Kettering Cancer Center in New York City, said.

“We have a long way to go. And I think we’ll be able to develop very effective therapies using this technology in the future.”

Three years after the first FDA approval of CAR-T cell therapy, patients with multiple myeloma are starting to see the therapy emerge in earlier lines. 

Moving Forward in Multiple Myeloma: Earlier Lines of CAR-T Cell Therapy

Dr. Debu Tripathy of The University of Texas MD Anderson Cancer Center and CURE Editor-in-Chief discussed the changing landscape as cancer vaccines enter the picture.

In the pursuit of groundbreaking cancer therapies, the spotlight has shifted to a promising frontier: cancer vaccines. In this issue, we explore the revolutionary potential of personalized mRNA-based vaccines as well as off-the-shelf options, offering a glimpse into the evolving landscape of immuno-oncology.

The combination of mRNA technology and immunotherapy, exemplified by mRNA-4157 paired with Keytruda (pembrolizumab), has emerged as a new potential treatment option for melanoma, with results from the landmark KEYNOTE-942 trial underscoring the efficacy of this combination. This is essentially a one-two punch of distinct pathways of the immune system — one mutation-specific and another that generates a broader immunological reaction.

“The main reason why this is exciting is the fact that this is the clearest sign that these vaccines can be likely active, and they can actually prevent a melanoma recurrence from happening,” said Dr. Patrick Ott, of the Dana-Farber Cancer Institute in Boston.

While researchers are pioneering personalized vaccines, such as mRNA-4157, that target unique mutations present in tumor cells, there have also been strides made in the development of off-the-shelf vaccines, such as ELI-002 2P, which is intended to enable a patient’s immune system to identify and destroy pancreatic and colorectal cancer cells with cancer-driving KRAS G12D and G12R mutations commonly seen in these cancer types.

The timeline for cancer vaccines’ general availability is unknown, with Dr. Jay Berzofsky of the National Cancer Institute telling 

such treatments won’t be available this year, or probably even next year.

“But, on the other hand, I think if something is really successful, the [Food and Drug Administration] has ways of fast-tracking approval,” Berzofsky said. “So, if there’s a real home run, then it might happen faster than we think, and that would be wonderful.”

We have come a long way in cancer immunology with newer discoveries of the intricacies of how our bodies recognize cancer cells and mount an immune response, along with innovative ways to boost that further. This is a result of sustained research with newer tools that will accelerate this trend. I suspect a growing fraction of the next generation of cancer drugs will be immunological.

Cancer vaccines, particularly personalized mRNA-based and off-the-shelf options, are emerging as promising therapies in immuno-oncology. The combination of mRNA technology and immunotherapy, such as mRNA-4157 with Keytruda, shows potential in treating melanoma, as demonstrated in the KEYNOTE-942 trial. Personalized vaccines target unique tumor mutations, while off-the-shelf vaccines like ELI-002 2P aim to combat common mutations in pancreatic and colorectal cancers. Although general availability timelines are uncertain, successful outcomes could expedite FDA approval, potentially revolutionizing cancer treatment.

With many groundbreaking cancer therapies on the horizon, it's also time to focus on up and coming cancer vaccines. 

Shifting the Spotlight to Cancer Vaccines

"In the landscape of cancer treatment, stories of dedication and breakthroughs often intertwine, offering hope amid the challenges faced by patients." 

Professor of Medicine Chair, Department of Breast Medical Oncology
The University of Texas MD Anderson Cancer Center

In the landscape of cancer treatment, stories of dedication and breakthroughs often intertwine, offering hope amid the challenges faced by patients. In this 

, we examine the impressive potential of antibody-drug conjugates (ADCs) in the treatment of bladder cancer, a class of drugs showing greater activity that we have seen with prior chemotherapy agents.

Antibody-drug conjugates, described by Dr. Yousef Zakharia of the University of Iowa as “targeted chemotherapy,” are designed to deliver a payload of chemotherapy directly to cancer cells, thereby intended to spare healthy cells from the impact of toxic treatments.

with the discovery of bladder cancer three years ago, leading to a series of treatments including surgery, chemotherapy and immunotherapy. Despite these efforts, she experienced multiple recurrences, but has had no evidence of disease for more than a year since starting treatment with Padcev (enfortumab vedotin-ejfv), an ADC that is reshaping the landscape of bladder cancer treatment.

Padcev’s transformative impact was high- lighted by the remarkable results of the EV-302 clinical trial, which revealed significantly improved outcomes compared to traditional chemotherapy, a near doubling of the median time to tumor progression.

Padcev and Keytruda (pembrolizumab) combination therapy 

by the Food and Drug Administration in December 2023 for patients with locally advanced or metastatic bladder cancer represents a pivotal event, one described as a “eureka moment” by Dr. Bamidele Adesunloye, medical oncologist at City of Hope Atlanta.

Yet, as Zakharia aptly notes, the quest for a cure remains ongoing. While ADCs represent a significant stride forward, they are not without their challenges. Unmet needs persist, reminding us of the imperative to continue the pursuit of innovation and progress in cancer care.

“Certainly, we are heading [in] that direction,” he said, “but we are far away from curing everybody.” Further innovations in the more precise delivery of increasingly more potent drugs directly to tumor cells while protecting normal cells and tissue are expected over time.

Debu Tripathy, M.D.

The ABCs of ADCs in Breast Cancer

Moving Forward in Multiple Myeloma: Earlier Lines of CAR-T Cell Therapy

Shifting the Spotlight to Cancer Vaccines

Reshaping the Landscape of Bladder Cancer Treatment

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