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OncoSec Researching Ability of PerkinElmer Imaging Platform to ID Non-responders to PD-1 Drugs

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NEW YORK (GenomeWeb) – Drug developer OncoSec will participate in a research collaboration to assess the feasibility of using an imaging-based test for predicting which patients are unlikely to respond to PD-1 targeting immunotherapies.

Under the partnership, the University of California, Los Angeles, will test patient samples provided by OncoSec using PerkinElmer's quantitative imaging platform to see if the test can differentiate responders to PD-1 targeting drugs from non-responders. PerkinElmer has developed the Vectra quantitative pathology imaging system, which measures the expressions and characteristics of proteins on tissue regions, which are then stained by immunohistochemistry. The collaborators will use this imaging-based platform to quantify and assess the density of cytotoxic T cells in tumor biopsies.

Nature recently published a series of papers investigating why some cancer patients respond to a type of monoclonal antibody, called PD-1 checkpoint inhibitors, and others don't. PD-1, or programmed cell death protein 1, when it interacts with a ligand expressed on tumor cells called PD-L1, has a negative impact on the ability of T cells to attack tumors. The Nature studies suggest that patients who are PD-1 positive and have substantial tumor-infiltrating lymphocytes (TILs) tend to respond better to this class of drugs than those who are PD-1 negative.

In one of the published papers, researchers led by UCLA's Paul Tumeh, used quantitative multiplex immunofluorescence, next-generation sequencing, and immunohistochemistry to analyze samples from 46 metastatic melanoma patients taken before and after they were treated with Merck's anti-PD1 therapy Keytruda (pembrolizumab). The study showed that patients who responded to the drug had higher numbers of cancer-killing T cells, as well as PD-1 and PDL-1 expressing cells, inside tumors and in the invasive tumor margin – the area of the tumor most likely to metastasize. 

Tumeh and colleagues developed a predictive model based on CD8 expression at the invasive tumor margin and validated it in a 15-patient cohort. "Our findings indicate that tumor regression after therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated immune resistance," the researchers wrote in their paper. Robert Pierce, OncoSec's chief scientific officer and a former executive director within Merck's pathology department, was a co-author on the Nature paper.

"There is a lot of excitement around PD-1 [targeting] drugs," Tu Diep, OncoSec's VP of operations, told GenomeWeb. "The big question with these drugs is who are the patients that respond and who are the patients that don't. … Understanding the responder and non-responder phenotype is a real unmet need for the cancer community right now."

Diep noted that the different research teams that investigated this problem and published their findings in Nature essentially came to the same conclusion that for patients to respond to PD-1 targeting drugs their tumor cells have to be inherently equipped with immune cells. "The tumor has figured out a way to hide from the immune cells so that they aren't able to recognize the tumor and kill it," he said. "That’s where the PD-1 drugs are really exciting, because they are able to uncloak the tumor and allow the immune cells to kill the tumor." In patients who don't respond to PD-1 targeting drugs, they lack the immune cells to begin with, he explained.

In its latest collaboration with UCLA and PerkinElmer, OncoSec is planning to advance the findings of the Nature paper. OncoSec will provide UCLA with patient samples it has collected through its internal research programs. The university researchers will analyze those samples using PerkinElmer's platform and evaluate them in a manner similar to that employed by Tumeh and colleagues, and hopefully further validate their findings.

OncoSec is currently focused on investigating strategies to improve cancer patients' response to immunotherapies. If the research collaboration with UCLA and PerkinElmer yields positive results, the company will pursue development of a predictive diagnostic that differentiates responders from non-responders. Doctors could use the tool to figure out which patients need an immune-enhancing agent to turn them from non-responders to PD-1 drugs into responders.

The flagship program at OncoSec is for an investigational agent called ImmunoPulse, which is designed to deliver interleukin 12 (IL12) – a protein that upregulates the immune system – directly into the tumor. By doing so, the ImmnoPulse aims to boost tumor immunogenicity by increasing tumor infiltrating lymphocytes (TILs) and cancer-killing T cells, but without the related toxicities of IL12 treatment.

The company recently announced a partnership with the University of California, San Francisco to evaluate whether more metastatic melanoma patients will benefit from treatment with Merck's Keytruda when it is combined with ImmunoPulse. Keytruda is the first anti PD-1 drug approved by the FDA in September for advanced or unresectable melanoma patients who are no longer responding to other therapies.

However, the data on Keytruda suggest that predictive strategies are needed to identify those who don't respond to PD-1 targeting agents. The FDA approved the drug based on data showing that 24 percent of the approximately 80 patients who received Keytruda at the recommended dose experienced tumor shrinkage.

Merck is providing Keytruda – priced at $12,000 per month – for free for the OncoSec and UCSF study. However, according to Diep, there is no official agreement between OncoSec and Merck tied to the outcome of the trial.

Still, the study results would be of interest to Merck and numerous other drug firms racing to bring PD1-targeting drugs to market. Merck for one is focused on strategies to differentiate between responders and non-responders to Keytruda. For example, in advanced lung cancer, Merck is studying how well patients with varying levels of PD-L1 expression respond to the drug as a standalone treatment and in combination with other agents.

OncoSec is free to share the data of its ongoing study with UCSF looking at the ImmnoPulse and Keytruda combination with Merck and its competitors. This freedom gives OncoSec a significant bargaining chip.

For the time being, however, OncoSec will not be using PerkinElmer's device to preselect patients for the ImmunoPulse/Keytruda combination study with UCSF. However, OncoSec will likely use the imaging system to look at patients' samples retrospectively and confirm the findings of the UCSF study. "PerkinElmer's device hasn't been approved yet, so to use it as a preselection tool wouldn't be kosher with the US Food and Drug Administration," Diep noted. "However, samples from our study [could be used] to provide the data to validate a test in the future."

Ultimately, OncoSec's goal is to demonstrate that non-responders to PD-1 drugs, who don't have the necessary immune cells to experience a treatment benefit, become responders to such therapies after they receive ImmunoPulse and their immune system is upregulated. If studies show that ImmunoPulse can convert non-responders to PD-1 drugs into responders "then it will be very important for the medical community to identify ahead to time whether patients will respond to these drugs before they get it," Diep said.

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