Effectively harnessing the immune system requires activation of natural killer, dendritic, and T cells. NantKwest is developing off-the-shelf therapies that have shown great promise in initial clinical studies.

Emilie Branch, editor at Pharma’s Almanac, sat down with NantKwest’s Chairman and CEO, Dr. Patrick Soon-Shiong, to discuss this exciting treatment option and find out why it could be one of the most promising developments in oncology to date.

Immune Systems Rely on Triad of Cells

The immune system comprises a triad of cells that act in concert to kill cancer. Of these, natural killer (NK) cells are most important in the initial activation of the immune system. NK cells recognize compromised cells — cells from the body that have been infected or cells that are precancerous or cancerous. Notably, recognition occurs without the need for any specific receptor. The other cells in the immune system triad are T cells, which are trained to attack the compromised cells identified by the NK cells, and dendritic cells, which train T cells. Without crosstalk between these three cell types, it is not possible to achieve optimal treatment results.

Triple-Triangle Offense

To successfully treat cancer patients, therefore, it is necessary to adopt a coordinated approach to leveraging the immune system in an integrated fashion. The “triple-triangle offense” being developed by NantKwest is intended to induce immunogenic cell death leading to durable responses, even among challenging patient populations.

The company’s vision is to activate the three types of immune cells (which everyone is born with) in a quasi-simultaneous manner using one protocol to change the outcomes for cancer patients. NantKwest's approach combines cell therapy using engineered, off-the-shelf (allogeneic) NK cells with an IL-based fusion protein to activate the T cells — and a cancer vaccine based on an adenovirus (developed by sequencing mutations) to activate the dendritic cells that train the T cells.

Low-Dose, Outpatient Approach

The triple-triangle offense approach is based on the behavior of NK cells, as they are programmed to kill, and assumes that all three types of cells are needed to achieve durable, complete remission. Therefore, the use of checkpoint inhibitors that only activate T cells is insufficient for the long-term treatment of cancer. In addition, high-dose chemotherapy that leads to the destruction of NK cells and T cells makes little sense and may actually have negative consequences. On the other hand, the use of certain chemotherapy agents at low doses has the potential to unveil and unlock tumors and their hidden receptors.

Carefully harnessing NK cell, dendritic cell, and T cell activation is a safe immunotherapy regimen that can be administered in the outpatient setting. There is promising activity across multiple tumor types that avoids the ravages of high-dose chemotherapy.

Focus on Natural Killer Cells

The first natural killer cells were identified in 1992 in a patient from British Columbia. These cells were isolated and genetically engineered to recognize any tumor type regardless of the patient, providing the first allogeneic NK92 cells.

It was observed that NK cells that were activated and that incorporated specific high-affinity binding receptors could better mediate cancer killing. NantKwest has thus engineered high-affinity NK cells to leverage advanced therapies already on the market.

The first engineered NK cells (haNK^®) have high-binding-affinity CD16 receptors, which bind IgG1 monoclonal antibodies (mAbs), such as Herceptin (trastuzumab), Rituxan (rituximab), and Humira (adalimumab), after they have been attached to cancer cells, enabling antibody-mediated killing. taNK^® cells are NK cells engineered to incorporate chimeric antigen receptors (CARs) that bind to tumor-specific antigens found on the surfaces of cancer cells. t-haNKs^™ combine the haNK and taNK platforms in a single cell, providing innate, antibody-mediated, and CAR-directed killing in one cell therapy.

Notably, NantKwest’s activated NK cells only contain awakened receptors and do not express killer inhibitory receptors (KIR), which can be exploited by diseased cells to evade the killing function of NK cells. The company’s NK cells also carry more granzyme- and perforin-containing granules, thereby enabling the delivery of a far greater payload of lethal enzymes to multiple targets.

Unlike CAR-T cell therapies, which are personalized (autologous) medicines that require the collection of patient blood cells and individual processing per patient, NantKwest’s Living Drugs in a Bag^® produces an off-the-shelf therapy that can be produced in large multi-dose batches. This approach enables reduction of the risk of serious, excessive immune responses that have been associated with CAR-T cell therapies

Two-Company Collaboration

NantKwest is collaborating with clinical-stage immunotherapy company ImmunityBio on the development of combination therapies utilizing their NK cells. ImmunityBio has a broad portfolio of biomolecules designed to activate endogenous NK and CD8⁺ T cells and to develop a T cell memory cancer vaccine to combat multiple tumor types without the use of high-dose chemotherapy. Together, the companies have partnered with oncologists to create a self-contained ecosystem ideally positioned to create a new paradigm in cancer treatment.

Manufacturing Platforms

NantKwest has full GMP capabilities for NK cell production and more than one trillion NK cells in storage in a frozen state. ImmunityBio has also achieved a full-scale manufacturing process under GMP for the fusion protein (IL-15 superagonist N-803). Development of a manufacturing process for the production of the novel adenovirus we have developed as the third leg of the triple treatment is underway.

Promising Initial Results

NantKwest has already conducted several phase I/II clinical trials in patients with multiple tumor types. Infused NK cells have been well-tolerated, with no immune-related events other than fevers, which are desirable because they indicate activation of the immune system.

Patients with third-line Merkel cell carcinoma and fourth-line head and neck cancers treated with haNK CD-16 NK cells combined with Pfizer’s PD-L1 antibody, Avelumab, and with ImmunityBio’s N-803, an IL-15 superagonist, showed durable complete responses. Similarly, patients with triple-negative breast cancer (TNBC) who previously had failed all standards of care therapy for breast cancer demonstrated durable (median progression-free survival exceeding 13 months compared with historical controls of approximately three months), complete responses when treated with PD-L1.taNK NK cells, Avelumab, and N-803. Furthermore, after five infusions of PD-L1.t-haNK and N-803, a patient with metastatic pancreatic cancer who had failed standard of care experienced complete resolution of tumor metastasis.

These trials involved the world’s first combination of off-the-shelf NK with checkpoint inhibitor plus antigen simulation via adenovirus, to induce immune system activation. Achieving these promising results in patients with advanced stages of such highly aggressive cancers supports the hypothesis that using the tumor itself as a source of antigens and orchestrating NK cells and T cells will induce immunogenic cell death.

Devising a Path Forward

Based on these early-phase clinical results, NantKwest plans to initiate registration trials in recurrent metastatic TNBC and pancreatic cancer patients who have failed the standard of care. They also intend to apply for Breakthrough Therapy Designation for advanced TNBC and pancreatic cancer.

ImmunityBio has already received Breakthrough Designation from the FDA for BCG-unresponsive CIS non-muscle-invasive bladder cancer, and are expecting results from a trial involving more than 200 patients. We anticipate submitting registration filings with the FDA for bladder, lung, Merkel cell, and pancreatic cancer over the next five years.

By leveraging an integrated and extensive genomics and transcriptomics discovery and development engine, together with a pipeline of multiple, clinical-stage immuno-oncology programs, NantKwest is uniquely positioned to be a premier immunotherapy company.