Focus Feature on Cancer
Progress on women’s cancers
Scientists explore ‘zombie’ cells in cervical cancer and use light to improve ovarian cancer treatment
Gynecologic cancers can be some of the more vexing cancers in women. Yes, lung cancer, breast cancer, colorectal cancer, and pancreatic cancer are the most deadly cancers for women (in that order), but right after pancreatic cancer on that list is ovarian cancer, the deadliest of the gynecologic cancers. In part, that mortality rate is because only about 15 percent of ovarian cancers are diagnosed at an early stage of the disease.
And while cervical cancer is one of the more easily treated cancers of the female reproductive system when caught early—and it is more often caught early than ovarian cancer—the numbers still aren’t terribly promising. When detected at an early stage, the five-year survival rate for women with invasive cervical cancer is 92 percent, but roughly 44 percent of women are diagnosed at an early stage. That means more than half of woman are not diagnosed early, and if cervical cancer has spread to surrounding tissues or organs and/or the regional lymph nodes, the five-year survival rate drops to 56 percent. If the cancer has spread to a distant part of the body, the five-year survival rate is a mere 17 percent. And cervical cancer is the most common gynecologic cancer.
While breast cancer captures much of the news coverage and scientific funding, it is not a distinctly female cancer, and so we thought we would share two recent breakthroughs related to cervical and ovarian cancer.
Zombie cells and cervical cancer survival
According to scientists at the Medical College of Georgia (MCG), how well women with cervical cancer respond to treatment and survive the cancer correlates with the level of 10 proteins in their blood that also are associated with a “zombie” cell state more technically known as senescence.
The researchers studied pretreatment levels of these proteins in the blood of 565 women with stage 2 and stage 3 cervical cancer, who received standard treatments of internal radiation (brachytherapy), external radiation, or both. They found that women with low levels of the proteins secreted by senescent cells had higher survival rates than those with high levels of these senescence-associated secreted phenotypes (SASPs).
They also discovered that brachytherapy, which involves implantation of a radiation source near the cervix, greatly improved survival of patients who had high levels of these SASPs; however, it had little impact on those with low levels.
“These results demonstrate that cellular senescence is a major determining factor for survival and therapeutic response in cervical cancer, and suggest that senescence reduction therapy may be an efficacious strategy to improve the therapeutic outcome of cervical cancer,” the authors of the study, titled “Senescence-associated secretory phenotype determines survival and therapeutic response in cervical cancer,” wrote in the journal Cancers.
“We want to figure out how we can treat cervical cancer better than we do. Beyond stage and treatment modality, what other factors are playing a big role in determining which patients survive and how they respond to radiation therapy,” said Dr. Jin-Xiong She, the study’s corresponding author. She is also director of the MCG Center for Biotechnology and Genomic Medicine the medical school’s Georgia Research Alliance Eminent Scholar in Genomic Medicine. “The most important conclusion of our paper is you want to manage senescence to improve therapy for cervical cancer.”
When it comes to women who have high levels of SASPs in their blood, Dr. Sharad Purohit—a biochemist in the MCG Center for Biotechnology and Genomic Medicine and the study’s first author—noted that one strategy may be to use a class of drugs called senolytics. These therapeutic compounds target the senescent “zombie” cells for elimination and are under study to improve age-related disease. Purohit does emphasize that such a therapeutic course would be for adjunct therapy in conjunction with other more direct therapeutic modalities.
While cervical cancer is largely preventable thanks to regular Pap smears that can detect early, precancerous changes, or by vaccines against HPV, survival rates for those who get the disease have been stagnant for decades, the scientists noted. In fact, survival rates of the most common cancers have improved since the mid-1970s, with the exception of cervical and endometrial cancer.
To tackle the problem of improving cervical cancer treatment, the team first looked at blood levels of a total of 19 proteins they had found secreted by cells in a pathological site like a precancerous or cancerous cervix—although why the proteins are made is a question they can’t yet answer, says Purohit. They found that levels of 10 of the proteins had an impact on cervical cancer survival in the women, who were an average of 49 years old. All 10 proteins were associated with cellular senescence, either as the largely destructive and inflammatory SASPs themselves or involved in regulating SASPs.
While cancer cells more typically are associated with rapid reproduction that enables cancer’s growth, senescent cells cannot divide and reproduce. But She categorizes the proteins these senescent cancer cells are secreting as “bad stuff,” which helps create an inflammatory state in which cancer thrives and helps lay the groundwork for the cancer to migrate and metastasize. It also provides some protection from radiation therapy, which like chemotherapy works in part by killing off typically rapidly dividing cancer cells.
“The senescent proteins really change how cancer cells may respond to therapy,” She points out.
Shining a light on ovarian cancer
Research at Purdue University is indicating that shining a light on ovarian cancer—literally—might improve treatment choices for said cancer. As they note in their research, nearly 60 percent of cancer patients fail to respond to chemotherapy treatments. But now, a Purdue University scientist and entrepreneur is working to use simple LED light to help determine if certain chemotherapy options will work for specific patients. The work was published in Scientific Reports under the title “Intracellular optical doppler phenotypes of chemosensitivity in human epithelial ovarian cancer.”
As the authors noted in their paper, “Development of an assay to predict response to chemotherapy has remained an elusive goal in cancer research. We report a phenotypic chemosensitivity assay for epithelial ovarian cancer based on Doppler spectroscopy of infrared light scattered from intracellular motions in living three-dimensional tumor biopsy tissue measured in vitro.”
As explained a bit more succinctly by David Nolte, the Edward M. Purcell Distinguished Professor of Physics and Astronomy in Purdue’s College of Science, the technique is very similar to Doppler radar used in weather forecasting. Except in this case, it is being used to advance personalized medicine.
“We take the LED light and shine it on biopsies,” Nolte explained. “We then apply chemotherapy to the biopsies and analyze how the light scatters off the tissues.”
Nolte, who also is a member of the Purdue University Center for Cancer Research, said the light-scattering dynamics give scientists and doctors detailed information about the likelihood of a chemotherapy drug being effective for a patient. Nolte said they have results within 24 hours. This first trial looked at biodynamic imaging on human patients with ovarian cancer.
“We look for signs of apoptosis, or what we call the controlled death of cells,” Nolte said. “Apoptosis is the signal that indicates the effectiveness of the chemotherapy for this patient’s tissues and tumors. For some cancers, there are so many treatment options available that it’s like a doctor is trying to fit square pegs in circular holes until a desired outcome is found. We want to make this process better for patients.”
Direct treatments for ovarian cancer
Before we leave the topic of ovarian cancer, it is worth sharing some recent clinical trial updates in this area.
First, the end of 2020 brought news from SELLAS Life Sciences Group, a late-stage clinical biopharmaceutical company focused on the development of novel cancer immunotherapies for a broad range of cancer indications, that early data from a study of galinpepimut-S (GPS) in combination with Keytruda showed a disease control rate of 87.5 percent at a median follow-up of 9.4 weeks and progression-free survival of 100 percent at six weeks.
The trial is part of a pair of clinical studies—the other involving mesothelioma—of GPS, the company’s Wilms tumor-1 (WT1)-targeting peptide immunotherapeutic, in combination with checkpoint inhibitor therapies.
More mature clinical and immunobiological data are expected to be announced by the end of the second quarter of this year, according to SELLAS.
In both studies, the safety profile of the combination of GPS with the checkpoint inhibitor was similar to that seen with checkpoint inhibitors alone, with the addition of only low grade, transitory local reactions at the site of injection of GPS, consistent with previously performed clinical studies of GPS.
Meanwhile, late January brought news from Sutro Biopharma—a clinical-stage drug discovery, development, and manufacturing company focused on using protein engineering and rational design to create next-generation cancer and autoimmune therapeutics—that it had dosed its first patient in the dose-expansion cohort of its Phase 1 STRO-002 study.
STRO-002 is an internally developed, folate receptor alpha (FolRα)-targeting antibody-drug conjugate for the potential treatment of ovarian cancer.
“Results from our STRO-002 dose escalation in a heavily pretreated ovarian cancer patient population demonstrated improved outcomes in RECIST response and duration of response,” said Dr. Arturo Molina, chief medical officer of the company. “Sutro plans to expand the study to approximately 35 clinical sites in the US and Europe. We are hopeful that the dose-expansion study will validate the preliminary signs of efficacy we have seen in dose-escalation and provide valuable data on the treatment paradigm and patient population that will benefit from treatment, bringing us one step closer to offering an important new potential treatment option to ovarian cancer patients.”
“STRO-002 continues to be well-tolerated and we have observed encouraging preliminary activity in patients with advanced platinum-resistant and refractory ovarian cancer,” added Dr. Lainie Martin, leader of Gynecology/Oncology Program at Hospital of the University of Pennsylvania and an investigator on the STRO-002-GM1 study. “We are excited to be part of the STRO-002-GM1 dose-expansion study and to provide additional clinical data to show the potential of this therapeutic for ovarian patients with limited treatment options.”
AACR to hold its second virtual annual meeting
Last year, the American Association for Cancer Research (AACR) had to pivot quickly in the face of the COVID-19 pandemic and the risks of large public gatherings, and shifted from an in-person meeting to its first-ever AACR Virtual Annual Meeting—a meeting that attracted more than 61,000 registrants from 140 countries.
This year, with the pandemic a more serious concern than it was in spring 2020 when AACR made the change, the association will once again go virtual, with a meeting scheduled once again in two parts—the first to be held April 10-15 and the second to take place May 17-21.
“The AACR Annual Meeting is the most critically important cancer meeting in the world, as it brings together key stakeholders in all areas of cancer research to make connections, build collaborations, and explore and expand the frontiers of integrative cancer science and medicine,” the association noted in announcing its decision. “Our annual meeting is widely considered by the global cancer community to be the touchstone event that sets the cancer research agenda. We recognize that the presentation of new data, exchange of information, and opportunities for collaboration offered during the meeting are invaluable to the entire cancer research enterprise.
“Therefore, we are working actively to develop an interactive and comprehensive virtual meeting. Everything that you have come to expect from the annual meeting—cutting-edge science, practice-changing clinical trials, an exciting educational program, opportunities for networking and professional development, and the discussion of new research directions—will be included in the virtual format.”
The first week conducted in April will feature the opening ceremony, plenary sessions, major scientific sessions, and award lectures. All proffered abstracts that are accepted for presentation—including clinical trials and late-breaking abstracts—will also be presented in plenary sessions, minisymposia, and ePoster sessions during this week. The second week conducted in May will feature education sessions, methods workshops, meet-the-expert sessions, and professional advancement sessions.
Visit www.aacr.org/meeting/aacr-annual-meeting-2021 for more information about the event.
Commentary: What’s driving the oncology manufacturing market?
By Ann Fish-Steagall of Two Labs
As it currently stands, oncology makes up a large portion of new drug development; roughly one-third of the entire new product pipeline in the U.S. emerging pharma market involves oncology medications.
In my role of supporting pharma manufacturers—many of whom are emerging companies bringing their first product to market—I’ve noticed several trends that are influencing both the nature of the launches and the product themselves. While some of these trends are driven by the market, many are driven by the diseases we’re targeting.
As oncology patients and providers know all too well, cancer is not a one-size-fits-all disease, nor is it one to easily surrender. Fortunately, manufacturers are learning to adjust.
Rare, orphan diseases and small target populations
For patients, families, and even for us on the manufacturing side, cancer can seem ubiquitous. But what we also see from the manufacturer side is how truly rare some of the indications can be, which for us, translates into smaller populations that can be treated with a targeted therapy.
Because of these smaller target populations, we are seeing more drugs fast-tracked through clinical trial stages that—although they are essential for more common indications—can be irrelevant for rare and orphan diseases.
In a normal Phase 1 trial, we are looking for the maximum tolerated dosing, not necessarily drug efficacy. Patients will naturally segment themselves into groups based on efficacy and responsiveness, and then those that are responding well would move onto Phase 2. Now, with these highly targeted mutational indications that we’re working with, there is no reason to test the drug on a patient without the specific mutational tumor driver being addressed. Instead, we are only working with patients whom we expect to respond from the beginning.
We are seeing these shifts in trial design because of the small target populations we are addressing, but we have only seen the tip of the iceberg in identifying mutational drivers of malignant tumors. As important mutations are discovered, the pipeline for therapies to target those mutations will grow.
Shattering silos with immuno-oncology
A breakthrough in the way we understand cancer has led to the growing subset of immuno-oncology treatments. Learning why it is we can’t fight cancer the same way we would fight a cold or the flu has given us an increased understanding of the role of—and the effect on—the immune system. We now know that along with targeting the cancer itself, targeting the immune system to ‘unlock’ its healing potential is yielding better outcomes for cancer patients.
Previously, we saw clear-cut silos between immunotherapy trials and traditional oncology therapy trials. Because of the increased overlap of these two therapy areas and the resulting potential, we are seeing an increase in combination trials. Combining different mechanisms of action, focusing on fighting the cancer itself, and encouraging the body to also fight the cancer at the same time increases the patient’s potential for response.
Another subset we’re seeing growth and success in is cell and gene therapies that re-engineer the immune system, equipping them to better attack a given tumor. Currently, most of these therapies in the oncology space are CAR-T therapies. These therapies use T cells that have been removed from the patient, re-engineered with specific receptors (chimeric antigens), and then returned to the patient. Once they are re-introduced, the chimeric antigen cells seek specific tumor cells and attack them. Currently, the only approved CAR-T therapies are being used in blood cancers, but many clinical trials are underway with testing CAR-T therapy for solid tumor indications.
Generational mutations driving research cycles
The more we learn about tumor biology, the more drugs we’re developing that can target these rare but very specific mutations in a tumor. And again, I can’t stress how much the small target population is behind many of the trends we see. For example, there have been two lung cancer drugs recently launched and approved, both for the specific RET+ non-small cell lung cancer tumors, a mutation that only 5 to 8 percent of cancer patients possess.
Another trend is looking at tumor-agnostic mutations—mutations that may only occur in 1 percent or less of a certain tumor, but can occur in small populations across multiple tumor types. Clinical trials are being designed to span multiple tumor types that have these specific mutations, rather than concentrating on a specific organ of origin. Because of this, we are learning that it’s more about the mutation than the site of origin. Traditionally, trials were designed to accrue breast cancer or lung cancer or leukemia patients. In this new way to look at cancer, research trials are designed to accrue by the mutation.
On top of this, once we do the work and develop drugs that can target these specific mutations, we have to address the inevitable second generation of the mutation. As we treat and target a mutation, it will likely learn to outsmart the targeted therapy, so we have to develop second and third generations of drugs that target the mutated disease, which are called mutations of resistance. This constantly mutating process is just a natural phenomenon in diseases and viruses that we have to work with and anticipate. In many instances, research is conducted in anticipation of a second-generation before the first-generation therapy is even on the market.
Biggest hurdles
For the most part, the biggest hurdles for oncology treatments mirror the hurdles we see in the general pharmaceutical market.
From a clinical trial perspective, physician and patient education and access continue to be a hurdle—only 5 percent of patients who are eligible for a clinical trial enroll in them. That leaves a huge untapped pool of candidates who could benefit from the trial, support the research, and help complete clinical trials sooner.
The COVID-19 clinical trials are a good example of how this works. Because these trials have accrued patients faster than any trials in history, they will bring us a vaccine in record time. Unfortunately, the opposite is often true with most trials—lower and slower candidate recruitment leads to slower drug development.
From the physician education side, COVID could make it more difficult for pharmaceutical companies to contact physicians. In-person visits have mostly ceased, and speaker programs going virtual make it more difficult to know how well the education is received. There’s also the issue of institutional capacity and finding enough healthcare sites to reach candidates.
The other educational challenge is getting patients tested for the multitude of mutations that could be present. If the tumor is not tested and the mutations are unknown, it can’t be targeted. Educating treating physicians as well as pathologists is an important aspect of ensuring that the tumor drivers are identified in their patients.
And in between all this, how do we make patients aware of the options that are available to them? When I started in this industry, we only had a handful of drugs that we’d use for a number of oncology indications, and since then, that number has rapidly grown. It’s incredibly important for patients to know what drugs are out there, and both providers and manufacturers would agree that an engaged patient—one who is aware of their options—is ideal. Manufacturers are making significant efforts with speaker programs and other education efforts, and amid COVID, I’m seeing them innovate on these efforts.
Thanks to oncology researchers unlocking clues about how to understand and overcome cancer, and those in the pipeline process optimizing trial and launch procedures, oncology manufacturers stand to make great progress—on top of what they already have—in the coming years. We would also be remiss if we did not thank all of the courageous patients who enroll in clinical trials so that others may benefit.
Ann Fish-Steagall is senior vice president of specialty pharmacy at Two Labs and an oncology clinical specialist
A possible boon for cancer vaccines thanks to COVID
The rapid advancement of mRNA vaccine development in recent months, as part of attempts to halt the COVID-19 pandemic, is expected to “continue to break barriers in the pharmaceutical industry,” according to data and analytics company GlobalData—and the oncology market may be the one most likely to benefit.
Noted Miguel Ferreira, an oncology and hematology analyst at GlobalData: “mRNA vaccines were among many novel drug classes of interest for future drug development in oncology indications. However, historical clinical and regulatory barriers prevented this particular drug class from advancing much further until the pandemic paved the way for mRNA vaccines into the pharmaceutical industry.”
Currently, there are 44 ongoing clinical trials exploring mRNA vaccines, of which 48 percent are for oncology indications, where the highest stage of development is Phase 2, comprising 33 percent of these oncology clinical trials. Therefore, mRNA vaccines are still in early development for oncology, but a significant increase in development is expected in the near future, particularly from companies already set to benefit from the COVID-19 mRNA vaccines.
“BioNTech and Moderna are both set to profit from their investment into the COVID-19 market and interestingly, both companies were already co-developing cancer-related mRNA vaccines with the pharmaceutical giants Roche and Merck Co, respectively, and are likely to pioneer a new competitive landscape in the oncology market with their mRNA vaccines,” said Ferreira.
GlobalData maintains that BioNTech is in a particularly strong position, with six ongoing trials and a further three planned. It is also pioneering two distinct approaches: an off-the-shelf vaccine that targets several antigens and a personalized vaccine targeting a unique set of antigens specific to each patient.
“Both BioNTech and Moderna have valuable experience in this area, including in trial design and patient recruitment, and currently appear to be most likely to gain the first approval for an mRNA-based cancer vaccine,” said Dr. Jessica McCormack, another oncology and hematology analyst at GlobalData. “Both companies [have] expertise with both personalized and universal vaccines, which they are testing in a range of cancers, meaning that they will be well placed to focus on whichever area appears most promising.”
It will be important to understand if a personalized approach will be necessary, GlobalData notes, as this will significantly impact both development and approval timelines—so far, the personalized vaccines appear to be more effective.
“While the approval process would be more complicated for a personalized vaccine, we have seen approvals of personalized therapies in the past,” McCormack said. “Historically, there has been some skepticism around the use of cancer vaccines, but should the clinical data be positive, mRNA-based vaccines could significantly increase vaccine use in the oncology sector.”
Endoxifen breast cancer study halted early on positive results
Atossa Therapeutics, a clinical-stage biopharmaceutical company with a current focus on breast cancer and COVID-19, recently announced that based on substantially positive results achieved with the patients enrolled to date in its Australian open-label Phase 2 clinical study of oral endoxifen administered in the “window of opportunity” between diagnosis of breast cancer and surgery, Atossa has halted the study.
“It is a welcome event to halt an ongoing clinical trial because the results are so overwhelmingly positive,” said Dr. Steven Quay, Atossa’s president and CEO. “Data from the first six patients in our Australian Phase 2 window of opportunity study shows a 74-percent average reduction in Ki-67, which is a common measure of tumor cell activity, and that at the time of surgery all patients had Ki-67 levels lower than 25 percent, which is an important threshold to improve long-term survival as identified in studies by others.
“We believe that additional enrollment will not alter these positive results so we are terminating the study early. This saves at least a year on the development timeline, allowing us to accelerate clinical development in the Unites States.”
Atossa is evaluating a number of potential clinical benefits and potential indications for its oral endoxifen in the window of opportunity setting. These may include avoidance of surgery in some patients, such as older and/or frail patients, allowing for breast conservation surgery—as well as use of endoxifen in place of other neoadjuvant therapies such as chemotherapy, aromatase inhibitors, and other endocrine therapies like tamoxifen.
Developing novel T cell-engaging antibodies for cancer
The University of Texas MD Anderson Cancer Center and Xencor Inc. have announced a strategic research collaboration and commercialization agreement to develop novel CD3 bispecific antibody therapeutics for the potential treatment of patients with cancer.
This collaboration joins Xencor’s innovative XmAb technology and protein engineering expertise to create bispecific antibodies with MD Anderson’s expertise in the research and discovery of novel therapeutic antibodies, including the Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform, part of MD Anderson’s Therapeutics Discovery division.
“Xencor’s modular antibody engineering platform enables the rapid generation of XmAb bispecific antibodies, and our research collaboration with MD Anderson will further expand the use of our technology to explore novel therapeutic targets, which could result in the creation of new therapies for patients with cancer,” said Dr. John Desjarlais, senior vice president and chief scientific officer at Xencor.
T cell-engaging bispecific antibodies are designed to recognize and bind to an antigen on tumor cells as well as an activating receptor on T cells, such as CD3, in order to directly recruit and activate T cells against tumor cells. Xencor’s modular scaffold for engineering bispecific antibodies is the XmAb bispecific Fc domain, which reportedly enables the rapid creation of stable antibodies with novel antitumor mechanisms of action.
“There is an urgent need to discover new therapeutic targets and to develop antibody-based strategies to trigger an immune response against the tumors that express them,” said Dr. Dongxing Zha, institute head of the ORBIT platform at MD Anderson. “Xencor’s multiformat-capable CD3 bispecific antibody platform enables us to rapidly develop and investigate therapies against intriguing tumor targets, and we look forward to evaluating the first candidates to be engineered as part of this collaboration.”
MD Anderson will work to identify and develop potential antibodies, collaborating with Xencor to apply its XmAb bispecific technology to create therapeutic candidates. MD Anderson will then conduct and fund all preclinical activities to advance candidates toward clinical studies.
Xencor has certain exclusive options to license worldwide rights to develop and commercialize potential new medicines arising from the research collaboration. For programs not licensed by Xencor, Xencor will receive a portion of future payments received by MD Anderson. Xencor and MD Anderson are entering into the collaboration with two predetermined, undisclosed antibody candidates.
