Cue Biopharma Pioneers In Vivo T-Cell Enhancement
By Ed Miseta, Chief Editor, Clinical Leader
Cue Biopharma has quickly evolved into a player in the T-cell space. The company was formed in 2015, a spin-out from the Albert Einstein College of Medicine. Dan Passeri, the company CEO, has a background in oncology drug development and has worked at the National Cancer Institute. When he was asked to take over the firm in August 2016, he was employee number eight.
“Our technology is a protein engineering platform for designing biologics focused upon emulating nature’s “Cues” or signals for immune-modulation,” says Passeri. “Most of my career was spent in the area of small molecule development for blocking cancer-related pathways, not in immuno-oncology. What brought me to Cue Biopharma was the potential of using the platform for modulating the patient’s own immune system to eradicate cancer.”
Passeri believes the platform can stimulate a patient's immune system from within their own body and thereby harness the healing power of their immune system.
Before joining Cue Biopharma, the data emerging from immuno-oncology, namely checkpoint inhibitors, is what caught his attention. Passeri notes it was not the overall response rate of patients that intrigued him, but rather, he points to the durability of those responses. He was intrigued and excited by the idea that you can stimulate a patient's immune system against cancer so that the therapy itself is the patient’s own immune system.
“In my previous role as CEO of a cancer therapeutics company, we were developing small molecules against a number of cancer pathways,” he states. “I don't have an immunology background and to gain knowledge in the field, I spent a year on a sabbatical at Jackson labs and had the opportunity to work with Jacques Banchereau who's a well-known immunologist. When I came upon Cue Biopharma’s technology, I was amazed by how different it was from other therapies emerging, such as CAR-T or bi-specifics.”
A Different Approach
Passeri explains that checkpoints are signals used by cells to tell the immune system not to attack them. Cancer tumors can hijack that mechanism and cover themselves in checkpoint signals, thereby protecting themselves from the patient’s immune system. To effectively eliminate cancer, that protection must be overcome. For example, one approach used in immuno-oncology involves dosing a patient with an antibody that blocks those checkpoint pathways.
“Antibodies are injected to block that signal,” says Passeri. “However, if a patient is going to benefit from checkpoint blockade, the therapeutic benefit comes from there being a population of T cells already present that are trying to attack the cancer. Even if you remove the protection by blocking the checkpoint pathways, that treatment option relies on the existence of T-cells there to attack and kill the cancer. In the immuno-oncology space, researchers are trying to figure out how to speed up the activation and proliferation of those cancer relevant T-cells to attack the cancer.”
CAR-T treatments will take a patient’s blood, isolate the T-cells, genetically engineer them to identify a protein on the cancer, expand the number of cells, and then reinfuse those cells back into the patient.
That is where Cue Biopharma’s approach is different. The company’s technology uses a biologic that engages T-cells within the patient's body. It activates selective T-cells which can then attack the cancer once enough of them are produced. No blood is required to be taken out of the patient and there is no manipulation of T-cells outside the body. The therapeutic itself is the patient's own immune system.
“I believe this technology has the potential to be disruptive and transformative,” says Passeri. “By selectively engaging cancer specific T-cells directly in the patient’s body, we eliminated the logistical and manufacturing challenges of manipulating T cells outside the patient’s body, and thereby, can treat a patient without the time delays and cost.”
More Patient Friendly
Passeri notes performing T-cell manipulation ex vivo can take up to four weeks. Unfortunately for the patient, their cancer continues to grow during that delay. That procedure also involves infusing a huge number of cells into a patient that are not normally found in their body. Even then, those cells are only a fraction of the large population of cells that are relevant to the cancer. Cue Biopharma’s treatment removes the cost and downside of ex vivo T-cell manipulation while providing more convenience to the patient.
“Patients come in and receive a short infusion of the biologic,” says Passeri. “After that they are able to go home. After three weeks they come back for a second infusion where the physician is able to more closely control the dosing schedule based on what is observed in the patient.”
Passeri notes there is one possible downside to the treatment. Whenever a human is injected with a biologic that does not normally exist in the human body, there is a possibility of the body producing an immune response known as immunogenicity. That is something Cue Biopharma is monitoring, but thus far it does not appear any patients in the first few cohorts are showing any of these unwanted effects.
Cue Biopharma’s current Phase 1 trial is for head and neck cancer. The three patients recruited so far for the trial are refractory metastatic patients. They have already received a frontline therapy that they did not respond to or were resistant to. The patients are receiving escalating doses and are being observed for signs of toxicity and clinical activity.
Trial Design Raises Probability Of Success
When designing the trial, Cue Biopharma took a close look at inclusion and exclusion criteria. The FDA and payers want to know that new treatments will be beneficial to patients. It is not optimum or ideal to treat all patients with a drug if only 20 percent or 30 percent of them will respond to the therapy.
“Over the last several years, the FDA has clearly indicated they favor trials that stratify patients based on mechanistic rationale,” states Passeri. “For that reason, we have chosen to take a translational approach to our clinical trial design. We are testing patients before they receive our treatment to ensure they have the requisite characteristics to respond to the treatment. We will determine if a patient is likely to respond to the treatment based on molecular characteristics.”
Passeri notes the tumor in most head and neck cancer patients is driven by the human papilloma virus (HPV). Twenty years ago, that percentage was between 15 percent and 20 percent. Today, it is over 70 percent. Therefore, to enroll in the Cue Biopharma Phase 1 trial, the first criteria was to have head or neck cancer that was caused by HPV. If the patient is HPV positive, a second test is conducted to see if the tumor in those patients is driven by a specific virus known as P16. Finally, patients must have a specific genotype known as HLA-AO2.
“We are treating patients that are also known to be resistant to their frontline therapy,” adds Passeri. “By performing these tests, we have a much higher probability of treating patients that should respond to the treatment. If successful, we should see increased disease-relevant T-cells over the timeframe we are administering the drug to patients. Every six weeks we perform a scan on the patient's tumor. We expect to see the drug stimulating the immune system to work against the tumor.”
Of course, finding the right patients who fit the tight inclusion and exclusion criteria was another challenge. Passeri notes you first need to have connections with physicians who deal in head and neck cancer. The current standard of care for those patients is pembrolizumab, a PD-1 inhibitor that seems to be effective in approximately 25 percent of patients. Unfortunately, most of those patients will become refractory or resistant to the treatment.
“We have networked with premier cancer centers that specialize in treating those patients,” says Passeri. “That has made it easier for us to gain access to those patients. Those centers monitor their patients very closely, knowing that virtually all of them will become resistant over time. When we find the right patients, screening will begin to determine if they are a fit for our trial.”
The Future Of Clinical Development
Cue Biopharma’s own personnel played an instrumental role in designing the sophisticated trial and producing the inclusion/exclusion criteria. In fact, the company’s acting chief medical officer, Kenneth Pienta, is a practicing oncologist and an endowed professor at Johns Hopkins University. Pienta also played a key role in identifying the clinical centers that would take part in the trial. The company even met with key opinion leaders at those sites at an advisory gathering where the company explained the design of the treatment.
Still, Cue Biopharma is a small company of approximately 50 employees. That meant a CRO partner would be required to perform other aspects of the trial. The company was not looking for a large CRO but wanted one that was reputable and known for providing quality data and service. It settled on a midsized CRO that is now assisting with clinical metrics, gathering information, and managing patient data.
“We are proud of the trial we designed and are now conducting,” adds Passeri. “Once we see evidence of clinical response, we will be able to enhance that cohort from three patients to nine. This Phase 1 trial is going to provide us with a rich data set that will allow us to confidently interface with the FDA. We believe the evidence we gather will justify a Phase 2 expansion and an early registration path. We also believe the way we designed our trial and how it is being executed is the future of oncology clinical development. We are matching a drug’s mechanism of action with molecular profiling of patients. That will allow us to truncate the time and the number of patients required to demonstrate the advantages of a new treatment.”