case_images: PMC11813753_01
case_images: 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.
case_images: fonc-15-1472714-g002.jpg
case_images: PMC11813753_03_fonc-15-1472714-g002.jpg
case_images: f2
case_images: The patient's therapy continued from January to June 2020, including the therapeutics described above, as well as a single dose of capecitabine (500 mg PO) ( Supplementary Figure S2 ). CA19-9 levels over this treatment period remained under 1,000 U/mL ( Supplementary Figure S2 ).
case_images: PMC11813753_02
case_images: 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.
case_images: fonc-15-1472714-g002.jpg
case_images: PMC11813753_03_fonc-15-1472714-g002.jpg
case_images: f2
case_images: The patient's therapy continued from January to June 2020, including the therapeutics described above, as well as a single dose of capecitabine (500 mg PO) ( Supplementary Figure S2 ). CA19-9 levels over this treatment period remained under 1,000 U/mL ( Supplementary Figure S2 ).
case_images: 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.
case_images: fonc-15-1472714-g003.jpg
case_images: PMC11813753_04_fonc-15-1472714-g003.jpg
case_images: f3
case_images: In March 2020, second-line treatment with 5-FU, gemcitabine, and Abraxane was given ( Supplementary Figure S3 ).
case_images: PMC11813753_03
case_images: 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.
case_images: fonc-15-1472714-g001.jpg
case_images: PMC11813753_03_fonc-15-1472714-g001.jpg
case_images: f1
case_images: First-line therapy from July to October 2018 was FOLFIRINOX with Neulasta ( Supplementary Figure S1 ). August 2019. As second-line therapy, Abraxane and gemcitabine were given between July and September 2019. spIND therapy was initiated in November 2019 with the patient's consent and comprised PD-L1 t-haNK (2 x 109 cells/infusion IV), aldoxorubicin (80 mg/m2), cyclophosphamide (50-75 mg PO), N-803 (15 mug/kg sc), Abraxane (75 mg/m2), and gemcitabine (600 mg/m2) with a single instance of denosumab (60 mg) administration up to the end of 2019 ( Supplementary Figure S1 ).
case_images: 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.
case_images: fonc-15-1472714-g002.jpg
case_images: PMC11813753_03_fonc-15-1472714-g002.jpg
case_images: f2
case_images: The patient's therapy continued from January to June 2020, including the therapeutics described above, as well as a single dose of capecitabine (500 mg PO) ( Supplementary Figure S2 ). CA19-9 levels over this treatment period remained under 1,000 U/mL ( Supplementary Figure S2 ).
case_images: 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.
case_images: fonc-15-1472714-g004.jpg
case_images: PMC11813753_05_fonc-15-1472714-g004.jpg
case_images: f4
case_images: Abraxane therapy, as shown in  Supplementary Figure S4 . Disease progression was detected by a laparoscopic look in December 2019 and a slight decrease in lesion size by PET/CT in January 2020 ( Supplementary Table S2 ), at which time the highest ANC value was observed ( Supplementary Table S7 ). As fourth-line therapy, spIND therapy was initiated in January 2020 with the patient's consent and comprised Day 1 gemcitabine (750 mg/m2 starting, decreased to 600 or 300 mg/m2 on some occasions, IV) and Abraxane (100 mg/m2 starting and then decreased to 75 mg/m2, IV) followed by Day 3 PD-L1 t-haNK cells (2 x 109 cells IV), N-803 (15 mug/kg sc), and aldoxorubicin (80 mg/m2 starting and then decreased to 40-60 mg/m2) on a 1-week cycle until September 2020.
case_images: PMC11813753_04
case_images: 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.
case_images: fonc-15-1472714-g003.jpg
case_images: PMC11813753_04_fonc-15-1472714-g003.jpg
case_images: f3
case_images: In March 2020, second-line treatment with 5-FU, gemcitabine, and Abraxane was given ( Supplementary Figure S3 ).
case_images: 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.
case_images: fonc-15-1472714-g004.jpg
case_images: PMC11813753_05_fonc-15-1472714-g004.jpg
case_images: f4
case_images: Abraxane therapy, as shown in  Supplementary Figure S4 . Disease progression was detected by a laparoscopic look in December 2019 and a slight decrease in lesion size by PET/CT in January 2020 ( Supplementary Table S2 ), at which time the highest ANC value was observed ( Supplementary Table S7 ). As fourth-line therapy, spIND therapy was initiated in January 2020 with the patient's consent and comprised Day 1 gemcitabine (750 mg/m2 starting, decreased to 600 or 300 mg/m2 on some occasions, IV) and Abraxane (100 mg/m2 starting and then decreased to 75 mg/m2, IV) followed by Day 3 PD-L1 t-haNK cells (2 x 109 cells IV), N-803 (15 mug/kg sc), and aldoxorubicin (80 mg/m2 starting and then decreased to 40-60 mg/m2) on a 1-week cycle until September 2020.
case_images: PMC11813753_05
case_images: 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.
case_images: fonc-15-1472714-g004.jpg
case_images: PMC11813753_05_fonc-15-1472714-g004.jpg
case_images: f4
case_images: Abraxane therapy, as shown in  Supplementary Figure S4 . Disease progression was detected by a laparoscopic look in December 2019 and a slight decrease in lesion size by PET/CT in January 2020 ( Supplementary Table S2 ), at which time the highest ANC value was observed ( Supplementary Table S7 ). As fourth-line therapy, spIND therapy was initiated in January 2020 with the patient's consent and comprised Day 1 gemcitabine (750 mg/m2 starting, decreased to 600 or 300 mg/m2 on some occasions, IV) and Abraxane (100 mg/m2 starting and then decreased to 75 mg/m2, IV) followed by Day 3 PD-L1 t-haNK cells (2 x 109 cells IV), N-803 (15 mug/kg sc), and aldoxorubicin (80 mg/m2 starting and then decreased to 40-60 mg/m2) on a 1-week cycle until September 2020.