Research on the therapy was recently published in the peer-reviewed Journal for Immunotherapy of Cancer in April of 2020 titled, “Overcoming Hypoxia-Induced Functional Suppression of NK Cells.”
California-based biotechnology company NantKwest (NASDAQ: NK) has announced plans to initiate a phase 2 clinical trial of a natural killer (NK) cell-based immunotherapy in conjunction with privately-held company ImmunityBio.
The randomized, open-label phase 2 study, which is expected to start in June of 2020, follows the complete response of a metastatic pancreatic cancer patient to an immunotherapy approach combining natural killer (NK) cells and a fusion protein of the immune-stimulating cytokine interleukin-15 (IL-15).
In their approach, natural killer cells, a white blood cell subpopulation typically associated with the innate immune system, were targeted against programmed death-ligand 1, a protein expressed on the surface of pancreatic cancer cells that negatively regulates the anti-cancer response of the immune system.
The natural killer cells were combined with an IL-15 superagonist manufactured by ImmunityBio, known as N-803, which promotes the expansion and activation of NK cells and CD8+ T cells without influencing immunosuppressive regulatory T cells. N-803 is engineered to have 30-times greater activity than natural IL-15 and can persist within the bloodstream for a longer period of time, offering a lengthier period of immune-boosting activity.
In the phase 1 clinical trial (NCT04050709), researchers tested the safety and preliminary efficacy of this treatment strategy in a patient with second-line metastatic pancreatic cancer, meaning that the combination therapy of PD-L1-targeted NK cells and N-803 was used as a secondary treatment after relapse following a previous standard-of-care therapy. Over 130 doses of the NK cells were successfully delivered to the patient without severe adverse side effects.
Chairman and CEO of NantKWest Patrick Soon-Shiong, M.D., announced the findings of the phase 1 trial at the J.P. Morgan Healthcare Conference in San Francisco. “We hypothesize that a common treatment protocol that harnesses both the natural-killer cell and the T cells could be effective in treating cancer across multiple tumor types. This has been supported by the early signals of safety and efficacy in Phase 1 and 2 studies of NantKwest’s natural killer cells in advanced cancers,” said Dr. Soon-Shiong.
After five infusions of the NantKWest’s NK cell therapy and N-803, the tumor metastases of a pancreatic cancer patient that had failed standard-of-care treatment completely resolved per initial and follow-up CT and PET scans.
In response to the success of his company’s treatment approach, Dr. Soon-Shiong stated, “We are extremely pleased that the FDA granted us this expanded IND authorization to initiate this novel immunotherapy treatment enabling the cross-talk of the innate natural killer system with the adaptive T cell. Achieving complete response in metastatic pancreatic cancer and durable, complete responses in metastatic TNBC patients that have failed all current standards of care is a promising finding which may further validate our approach to orchestrate both the innate and adaptive immune system.”
“Pancreatic cancer and TNBC are highly aggressive cancers with limited treatment options. These results are important, proof-of-concept supporting our hypothesis that comprehensively activating the immune responses of the NK, T and Dendritic cells, the “triangle offense”, would induce immunogenic cell death leading to durable responses, even among this challenging patient population. Based on these encouraging findings, we plan to initiate clinical trials to confirm efficacy in second-line metastatic pancreatic cancer and third-line Triple Negative Breast cancer,” continued Dr. Soon-Shiong.
The phase 2 clinical trial has received authorization from the United States Food and Drug Administration and will evaluate the comparative efficacy and overall safety of the NantKwest PD-L1 tumor-targeted natural killer cells (t-haNK) and ImmunityBio’s IL-15 superagonist N-803 with “aldoxorubicin HCI plus standard of care, versus standard-of-care chemotherapy for first- and second-line treatment of locally advanced or metastatic pancreatic cancer.”
According to NantKwest, “Each treatment setting, and first- and second-line or later maintenance, will be evaluated independently as Cohort A and Cohort B, respectively, with each Cohort having independent experimental and control arms. The study will initially enroll 268 subjects across both cohorts with the primary objective of comparative efficacy by progression free survival (PFS) per RECIST V1.1.”
“Secondary objectives include initial safety and additional efficacy measures, including overall response rate (ORR), complete response (CR) rate, durability of response (DoR), disease control rate (DCR), and overall survival (OS).”
The combination therapy has been used to treat four metastatic pancreatic cancer patients under single patient investigational new drug (IND) applications. Among the two patients “on treatment for an evaluable period,” one has experienced an “ongoing, durable, complete response six months after initial treatment,” and the other has had disease stabilization.
“Our results from expanded access use of PD-L1 t-haNK in combination with N-803 offer proof-of-concept that, together with these agents, the immune system may play a role to activate robust and durable responses in metastatic cancer patients who have failed all standard-of-care therapies,” stated Dr. Patrick Soon-Shiong, MD, Chairman and Chief Executive Officer of NantKwest and ImmunityBio.
“Based on these encouraging data, we are moving forward with a randomized Phase 2 program that will evaluate our immunotherapy combination on top of standard of care, compared to standard of care alone, in first- and second-line treatment settings.”
“This unique approach to orchestrating the innate and adaptive immune systems to induce immunogenic cell death may be an important new approach for pancreatic cancer patients—these being among the most challenging to treat with poor prognoses.”
“Abraxane, a protein-based nanoparticle that activates macrophages, was our first evolution in making an impact on pancreatic cancer. With this addition of PD-L1 t-haNK and N-803, we are hopeful that we can proceed to the next step of long-term remission in this difficult to treat disease. Adding a natural killer cell with a checkpoint via PD-L1 t-haNK and activating memory T cells via N-803 will complete the ‘triangle offense’ we are orchestrating.”
“The early results of complete response in one patient using the therapy on a compassionate use basis is encouraging and we are excited to initiate this trial involving other patients who suffer from pancreatic cancer,” Dr. Soon-Shiong continued.
Metastatic pancreatic cancer is an unresectable form of pancreatic cancer that involves the spread of cancerous tissue from the initial site of tumorigenesis within the pancreas to distant organs, blood vessels, bones, or lymph nodes. Since there are few symptoms of the disease in its early stage and no general screening tools for the early detection of pancreatic cancer, most pancreatic cancers are diagnosed at an advanced stage.
Imaging of tumors within the pancreas is challenging due to the location of the pancreas deep within the abdomen behind the stomach and underneath the liver. Symptoms are often vague, including weight loss, jaundice, loss of appetite, nausea, stool changes, and the onset of diabetes.
While surgery is the preferred treatment for early-stage pancreatic cancers, metastatic pancreatic cancers are primarily treated by chemotherapy intended to shrink the size of the tumors and slow cancer growth. Common chemotherapies include the nucleoside analog Gemcitabine, albumin-bound paclitaxel (Abraxane), and inhibitor of the epidermal growth factor receptor erlotinib (Tarceva).
NantKWest is a clinical-stage immuno-oncology company that develops natural killer cell-based cancer immunotherapies, including the cell therapy that is entering phase 2 trials for the treatment of pancreatic cancer. NK cells, a subpopulation of white blood cells historically associated with the innate immune system, are capable of detecting and destroying abnormally altered cells, such as those suffering from viral infection or the genetic changes associated with cancer.
NantKWest is developing three types of NK-cell based therapies: (1) antibody-mediated, (2) chimeric antigen receptor-directed, and (3) a combination of these approaches. Their NK cells are modified to lack the expression of immunosuppressive receptors known as Killer Inhibitory Receptors (KIR) and to bear higher levels of the molecules perforin and granzyme which are used to destroy target cells including cancer cells.
The antibody-mediated NK cells express cell surface receptors known as CD16 that bind monoclonal antibodies. When antibodies targeting proteins on the surface of cancer cells are used in combination, these NK cells can migrate to and destroy cancerous tissue.
The chimeric antigen receptor-directed cells bear highly specific receptor proteins, known as chimeric antigen receptors, that target unique molecules on the surface of cancer cells. The interaction between these NK cells and cancer cells leads to the destruction of cancerous tissue.
The patient with a complete resolution of metastatic pancreatic cancer was treated with NK cells combining both of these approaches and targeted against the cancer-associated protein PD-L1.
Pre-clinical models have previously used IL-15 to augment the anti-cancer response of CD8+ T cells, and a phase I clinical trial initiated in 2009 by the National Institutes of Health evaluated the efficacy of IL-15 for the treatment of metastatic renal cell carcinoma and melanoma. IL-15 signaling is known to have an important role in the development of NK cells and in the activation and proliferation of T cells and NK cells.
A related immune cell subset known as invariant natural killer T (iNKT) cells are also being evaluated as a potential therapy for solid tumors, and will be entering human trials in 2020.