A ‘shock and kill’ approach

Combo therapy could produce long-term HIV remission even without ART

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CULVER CITY, Calif.—Repeated co-dosing of N-803, an IL-15 superagonist, in combination with bNABs (anti-HIV broadly neutralizing antibodies) may facilitate long-term viral remission without antiretroviral therapy (ART), according to results from studies evaluating N-803 alone and in combination with bNAbs.
Presented for the Annual Conference on Retroviruses and Opportunistic Infections (an event held virtually this year because of the COVID-19 pandemic), the data revealed that non-human primates (NHP) with simian/human immunodeficiency virus (SHIV) dosed with N-803 may have long-term viral remission without using antiretroviral drugs.
The study results, titled “Combination IL-15 Therapy in a SHIV NHP Model,” were presented by Dr. James B. Whitney, an assistant professor of medicine at Harvard Medical School, and showed that SHIV-infected, antiretroviral therapy-suppressed rhesus macaques had viral remission in response to treatment with a combination of anti-HIV antibodies and ImmunityBio’s N-803, even after ART administration was stopped.
Nine of 13 NHPs whose viral load had been suppressed with conventional ART treatment showed improvement. The company believes that this could be a promising step toward curative HIV therapeutics in humans. In chronic viral infections such as HIV, N-803 may contribute to a “shock-and-kill” approach that can eliminate the chronic component of the virus.
In what he described as “a pathway to deactivate viral cells by stimulating the proliferation of killer cells that protect the body from cancer and other infections,” ImmunityBio CEO Dr. Patrick Soon-Shiong talked about how N-803 may change the paradigm of HIV treatment from lifelong suppression to durable cure. He explained that N-803 is an IL-15 superagonist that activates both the innate and adaptive arms of the immune system via natural killer cells and T cells. He added that current standards of HIV therapy require lifelong daily ART medication to suppress virus activity, but fall far short of a cure.
According to Soon-Shiong, “Almost 40 years after the HIV virus was discovered, it continues to claim more than a million lives worldwide annually. While antiretrovirals have improved patient outcomes and significantly decreased morbidity and mortality, there is neither a vaccine nor a cure for HIV infection. ImmunityBio is therefore searching for a solution that will impact the HIV reservoir. These studies demonstrate that combination therapy with N-803, ImmunityBio’s IL-15 superagonist which activates NK and DC8 T cells together with broadly neutralizing antibodies, may stimulate the immune system to enable immune control of HIV in the absence of antiretroviral treatment.”
More specifically, the study demonstrated that 69 percent of ART-suppressed monkeys treated with N-803 in combination with one or two bNAbs exhibited durable control of viremia following ART removal, with durability observed beyond 25 weeks. Additionally, NK cells in the blood showed peak activation at 48 hours post N-803 administration throughout the dosing period, memory T cells were preferentially activated by N-803, CD8+ memory T cells demonstrated more robust expansion during the dosing period and N-803 dosing was well tolerated.
Recently published data in Nature demonstrated that N-803 induces robust and persistent simian immunodeficiency virus (SIV) reactivation in the context of CD8 T cell depletion, stimulating SIV out of hiding, providing a novel “shock-and-kill” therapy for HIV cure research. These findings indicate the potential of new strategies to overcome HIV through a sequential action of shocking viral reservoirs out of hiding with N-803 and then killing these infected cells through the powerful immune response of natural killer, CD8 and memory T cells activated by the IL-15 superagonist, to potentially enable long-term viral control.
Soon-Shiong explained that N-803 had also proven effective in a first-in-human immunotherapy clinical trial combining an IL-15 superagonist with NantKwest’s off-the-shelf, PD-L1 tumor-targeted NK cells (NCT04050709) in a patient with metastatic pancreatic cancer who had relapsed after prior standard-of-care therapy. He anticipates “broad, universal treatments across tumor types, avoiding high-dose chemotherapy and radiation.”
In December 2019, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to N-803 for BCG-unresponsive CIS non-muscle invasive bladder cancer (NMIBC). Other indications currently at registration-stage trials include BCG-unresponsive papillary bladder cancer, first and second-line lung cancer, and metastatic pancreatic cancer.
ImmunityBio’s goal is to develop therapies, including vaccines, for the prevention and treatment of HIV, influenza and the novel coronavirus SARS-CoV-2. The company is filing an IND with the FDA for therapy for the coronavirus.

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