Case report: PD-L1-targeted high-affinity natural killer cells and IL-15 superagonist N-803-based therapy extend overall survival of advanced metastatic pancreatic cancer patients

Abstract

Background: Metastatic pancreatic cancer (mPC) is an aggressive form of cancer with a poor prognosis and few therapeutic options after failure of the second-line treatment. Induction of immunogenic cell death (ICD) by use of relatively low-dose chemo- or radiation therapy, enhancement of immune responses by the IL-15 superagonist N-803 (Anktiva^®), and targeting of programmed death receptor ligand 1 (PD-L1)-expressing cells may offer a therapeutic approach to refractory mPC with the potential to increase overall survival (OS).

Methods: From late 2019 to 2021, single-patient Investigational New Drug (spIND) protocols for five mPC patients were designed and approved that generally comprised combined Abraxane (nab-paclitaxel) and gemcitabine therapy with experimental therapeutics N-803, PD-L1-targeted high-affinity natural killer (PD-L1 t-haNK) cells, and aldoxorubicin, a serum albumin-binding doxorubicin prodrug. Some patients also received stereotactic body radiation therapy (SBRT), cyclophosphamide, pembrolizumab, nivolumab, and/or experimental ETBX-051 (brachyury) and/or ETBX-061 (MUC1) vaccines. Duration of spIND treatment and responses, for some patients including imaging and carbohydrate antigen 19-9 (CA19-9) levels, and OS from initial diagnosis and the start of spIND therapy were assessed.

Findings: The line/duration of spIND therapy was, for patients 1 through 5, respectively, second line/6.4 months, sixth line/3.5 months, third line/25.4 months, third line/7.4 months, and fourth line/23.2 months. OS from the commencement of spIND therapy was 13, 4.8, 26.9, 9, and 23.2 months, and OS from diagnosis was 22, 21, 42, 13, and 33 months for patients 1 through 5, respectively.

Conclusions: The OS from the initiation of spIND for all patients exceeded the reported OS for the greater-than-second-line mPC patients and, for four of five patients, second-line therapy. The OS of 13, 26.9, and 23.2 months for three patients is particularly notable. The findings here support the ongoing clinical investigations of N-803 and PD-L1 t-haNK cells in combination therapy.

Keywords: 3rd line therapy; N-803; PD-L1 t-haNK cells; advanced metastatic pancreatic cancer; low dose chemotherapy; multi-modal; orchestrated.

Figure 1

Rationale for multimodal therapy to establish immune memory. (1) Low-dose chemotherapy such as Nab-paclitaxel (Abraxane) and stereotactic body radiation therapy (SBRT) is anticipated to (2) reverse immunosuppression by M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) in the tumor microenvironment (TME). (3) The release of damage-associated molecular patterns (DAMPs) from dying tumor cells leads to upregulation of MHC-1, and often PD-1/PD-L1 expression, (4) activating the innate immune system. (5) Further upregulation of cell stress receptors and tumor antigens by aldoxorubicin and SBRT also contributes to activation of M1 macrophages, cytotoxic T, and natural killer (NK) cells, an effect that is enhanced by (6) the IL-15 superagonist N-803. PD-L1-targeted high-affinity NK (PD-L1 t-haNK) cells target and reverse immunosuppression. The goal is (7) dendritic cell (DC) maturation and activation, leading to establishment of memory T cells.

Figure 2

Metastatic pancreatic cancer (mPC) single-patient Investigational New Drug (spIND) patient 1 diagnosis and treatment history. mPC diagnosis (green box) in May 2019 was followed by first-line FOLFIRINOX treatment. Disease progression (red box) detected in February 2020 prompted initiation of a spIND protocol comprising Abraxane (orange), gemcitabine (dark green), cyclophosphamide (light yellow), PD-L1 t-haNK (red), N-803 (aqua), stereotactic body radiation therapy (SBRT; pink), aldoxorubicin (dark yellow), cisplatin (light green), and pembrolizumab (light blue) given on the days indicated. Dates of imaging are shown in black. CA19-9 levels (U/mL) from March to August 2020 are shown above the timeline.

Figure 3

Metastatic pancreatic cancer (mPC) single-patient Investigational New Drug (spIND) patient 2 diagnosis and treatment history. mPC diagnosis (green box) in February 2019 was followed by first-, second-, third-, fourth- (experimental SM-88 therapy), and fifth-line therapies up to June 2020, at which time the spIND protocol commenced comprising Abraxane (orange), gemcitabine (green), PD-L1 t-haNK (red), N-803 (blue), aldoxorubicin (yellow), and nivolumab (dark blue) given on the days indicated. There was evidence of disease progression (red boxes) and some response (gray box) on the dates shown. Dates of imaging are shown in black. CA19-9 levels (U/mL) in January 2020 and from August to September 2020 are shown above the timeline.

Figure 4

Metastatic pancreatic cancer (mPC) single-patient Investigational New Drug (spIND) patient 3 treatment history from late August 2020 until October 2021. The spIND protocol comprised PD-L1 t-haNK (red), N-803 (blue), Abraxane (orange), aldoxorubicin (yellow), ETBX vaccines 051 and 061 (purple), gemcitabine (green), nivolumab (dark blue), and capecitabine (gray), given on the dates shown; the patient also received a single dose of cisplatin (light green) and a single instance of stereotactic body radiation therapy (SBRT; pink). Disease regression is shown in gray boxes, disease progression in red boxes, and dates of imaging in black. CA19-9 levels (U/mL) from September 2020 to October 2021 are shown above the timeline.