Revolution in immuno-oncology

Intratumoral cancer immunotherapy enhances local delivery and uptake of DNA-based immune-targeting agents

Ilene Schneider
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SAN DIEGO—Based on the results of a study showing that therapies targeting the programmed death-1 (PD-1) receptor provide unprecedented rates of durable (long-lasting) clinical responses in patients with various cancer types, OncoSec Medical Inc. is collaborating with University of California, Los Angeles (UCLA) researchers and PerkinElmer Inc. to help develop biomarker tests to evaluate a patient’s immune response to cancer.  
The article in the November 27, 2014 issue of the journal Nature, titled “PD-1 blockade induces responses by inhibiting adaptive immune resistance,” showed the effectiveness of DNA-based intratumoral cancer immunotherapies that combat adaptive immunoresistance of cancer. Research led by Drs. Paul Tumeh and Antoni Ribas at UCLA—along with work conducted by Dr. Robert Pierce (currently chief scientific officer at OncoSec) and his colleagues at Merck Research Labs during his previous tenure as executive director at Merck—shows that the response to anti-PD-1 drugs is dependent on the presence of PD-L1 (PD-1 ligand) and tumor-infiltrating lymphocytes (TILs) in the tumor.
“OncoSec is trying to address the population of patients that doesn’t respond to PD-1 alone,” explains Punit Dhillon, president and CEO of OncoSec. “In immunotherapy, we need to understand how tumor biology works to go after rational approaches for combination therapies that will increase the response rate for various tumor types.”
According to Pierce, the approach represents “a revolution in immuno-oncology.” Immunotherapy is not simply directed at a particular tumor type, but the test will determine whether a patient has an immune phenotype that will respond to the therapy.
Dhillon adds, “Building on the pioneering work of Dr. Pierce while at Merck, we have focused the potential of ImmunoPulse therapy with IL-12 to enhance TILs in tumors to treat the larger population of cancer patients who are not responsive to anti-PD1 or other checkpoint inhibitors. We are very excited about the potential implications of a successful combination Phase 2b trial of Merck’s pembrolizumab and ImmunoPulse.”
OncoSec, a biopharmaceutical company developing investigational intratumoral cancer immunotherapy, offers core technology designed to enhance the local delivery and uptake of DNA IL-12 and other DNA-based immune-targeting agents. OncoSec’s proprietary technology platform, ImmunoPulse, prompts the body’s immune system to target and destroy both local and metastasized cancer cells. Using electroporation, ImmunoPulse delivers brief electrical pulses of DNA IL-12, which stimulates the patient’s immune system to destroy cancer cells. ImmunoPulse is designed to stimulate the body’s immune system and enable it to recognize, target and destroy cancerous cells.  
Clinical studies of ImmunoPulse have demonstrated an acceptable safety profile and preliminary evidence of antitumor activity in the treatment of various skin cancers, as well as the potential to initiate a systemic immune response without the systemic toxicities associated with other treatments. The company has clinical trials underway for melanoma, head and neck cancer and triple-negative breast cancer.
Tumeh and Ribas at UCLA were doing dermatology research on melanomas in a study of 46 patients with advanced melanoma treated with pembrolizumab. The patients underwent tumor biopsies before and during treatment. According to the study, the presence of PD-L1 in tumors alongside tumor-infiltrating CD8+ lymphocytes—a phenomenon that has been termed “adaptive immune resistance”—is a potential biomarker for predicting response to anti-PD-1 drugs. The researchers say that combining anti-PD-1 drugs such as pembrolizumab with therapies that can induce a type-1 interferon-gamma response should be further investigated.
“These data make an important contribution to our understanding of PD-1 inhibition,” according to Pierce. “Importantly, the correlation of low TILs with a lack of response to pembrolizumab drives home the need for new therapies that amplify TIL response in those low-TIL patients. We know that IL-12 drives a type-1 interferon-mediated immune response and augments TIL generation, supporting that the combination of ImmunoPulse IL-12 and PD1 blockade will lead to enhanced responses in melanoma.”
PerkinElmer has developed a new multiparametric immunohistochemical analysis platform consisting of its Vectra automated quantitative pathology imaging system and its Opal multiplex tissue staining assays, which together can help scientists perform biomarker research to develop a potentially predictive assay to identify the non-responder population. The company will collaborate with OncoSec and UCLA to help researchers develop biomarker tests to evaluate a patient’s immune response to cancer.  
“We’re excited, because it’s taken 100 years to get to this point,” Pierce says. “Even if only a subpopulation responds to the therapy, the patients respond for a long time. Now we can use biomarkers to tailor studies that will help to increase the response rate.”

Ilene Schneider

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