Research ArticleCancer

Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti–PD-1 for patients with anti–PD-1–refractory tumors

See allHide authors and affiliations

Science Translational Medicine  14 Oct 2020:
Vol. 12, Issue 565, eabb0391
DOI: 10.1126/scitranslmed.abb0391
  • Fig. 1 CONSORT diagram of patient screening and enrollment for each of the four treatment cohorts.

    Intratumoral BO-112 injections are indicated by red arrows. Patients treated in cohort 4 with nivolumab were treated with one dose of BO-112 before reintroducing nivolumab every 2 weeks, whereas patients on pembrolizumab were treated with two doses of BO-112 before reintroducing pembrolizumab every 3 weeks until progression or discontinuation. BO-112 injections were administered on the same day and before the anti–PD-1 intravenous infusion. Solid black circles represent tumor biopsies: “pre-treatment” biopsy was on day 1 in week 1 before BO-112 for cohorts 1 to 4; “post-treatment” was 7 days after the last BO-112 injection in cohorts 1 to 3 and on day 36 in week 6 before the BO-112 injection in cohort 4.

  • Fig. 2 Response assessments of patients treated in the combination cohort.

    (A) Waterfall plot for RECIST 1.1 best objective response. Waterfall plot is missing nine patients, because eight patients either died or had disease progression before the first scheduled response assessment, and one patient was not evaluable due to irradiation of his RECIST target lesion. (B) Modified swimmer plot for PFS. The shaded gray bars on the left side of the swimmer plot represent the anti–PD-1 agent exposure time (weeks) before study entry. Red asterisk corresponds to a patient that had a prestudy period >30 weeks. Swimmer plot is based on intention to treat and has all the patients. (C) CT scans of two of the three patients with objective response (basal scans on the left, first on-treatment evaluation scans at 9 or 10 weeks on the right). Top: Female patient with BRAF wild-type melanoma refractory to nivolumab. Bottom: Male patient with renal carcinoma refractory to sunitinib, cabozantinib, everolimus, and nivolumab. Yellow arrows indicate BO-112–injected lesions, and red arrows indicate noninjected lesions.

  • Fig. 3 Evaluation of immune cells in biopsies before and after BO-112 treatment.

    (A) Pre- and post-treatment intratumoral CD8+ and CD4+ T cell density in patients treated with the combination of BO-112 and anti–PD-1 agents in cohort 4. ns, not significant. (B) Representative IHC images showing CD8+ and CD4+ T cell infiltrates in two patients with PR and one patient with SD. Scale bars, 100 μm.

  • Fig. 4 Gene expression profiles upon BO-112 treatment.

    (A) Specific BO-112 gene expression signature obtained for the BO-112 plus anti–PD-1 combination cohort 4 (n = 17). The post-treatment expression profiles of these 10 genes allowed us to classify the patients according to their overall response assessment (RECIST 1.1), annotated in the top row (dark green, PR; light green, SD; gray, PD). (B) Volcano plot representing the changes in post-treatment gene expression when comparing tumor samples from patients who had PR or SD as best response with samples from patients whose best response was PD (no benefit) after treatment with intratumoral BO-112 and an approved anti–PD-1 antibody systemically (statistically significantly up- and down-regulated genes are depicted in red, −log10 [P value]). (C) Enrichment analysis of the specified gene signatures. The color scale associated with the heatmaps refers to the relative gene expression as compared to baseline (log2 [ratio]).

  • Table 1 Demographic, pathological, and clinical characteristics of patients treated in cohorts 1 to 3.

    CharacteristicsPart 1
    Cohort 1
    n = 6
    Cohort 2
    n = 7
    Cohort 3
    n = 3
    Total
    n = 16
    Median age, years (range)61 (49–73)58 (42–74)58 (46–78)58 (42–78)
    Male (%), female (%)2 (33), 4 (67)2 (29), 5 (71)1 (33), 2 (67)5 (31), 11 (69)
    Tumor type, n (%)
      Melanoma4105 (31)
      Leiomyosarcoma0213 (19)
      Breast carcinoma1102 (13)
      Other (adenoid cystic
    carcinoma, colorectal
    cancer, endometrial
    neuroendocrine carcinoma,
    head and neck cancer,
    ovarian cancer, and
    mesothelioma; n = 1 per type)
    1326 (38)
    Previous lines of oncology
    therapy, n (%)
      00000
      11102 (13)
      2 or more56314 (88)
    Previous radiotherapy, n (%)46111 (69)
    Site of target (injected) lesion,
    n (%)
      Skin/subcutaneous nodule2406 (38)
      Lymph node2204 (25)
      Soft tissue2024 (25)
      Liver0112 (13)
  • Table 2 Demographic, pathological, and clinical characteristics, including previous anti–PD-1 exposure of patients treated in cohort 4.

    SCCHN, squamous cell carcinoma of the head and neck; RCC, renal cell carcinoma.

    Cohort 4, n = 28
    Characteristicsn (%)
    Median age, years (range)59.5 (29.0–74.0)
    Male and female16 (57.1) and 12 (42.9)
    Tumor type
      Melanoma10 (35.7)
      NSCLC13 (46.4)
      SCCHN4 (14.3)
      RCC1 (3.6)
    Previous lines of oncology therapy
      06 (21.4)
      110 (35.7)
      2 or more12 (42.9)
    Site of injected lesion*
      Skin/subcutaneous nodule6 (21.4)
      Lymph node12 (42.9)
      Soft tissue—nonvisceral7 (25.0)
      Lung4 (14.3)
      Liver1 (3.6)
    Anti–PD-1 antibody
      Nivolumab20 (71.4)
      Pembrolizumab8 (28.6)

    *Eight patients (five with melanoma and three with NSCLC) had additional lesion(s) injected for some subsequent BO-112 administrations.

    †Two patients started nivolumab as part of a combination therapy rather than as single agent (one with daratumumab and one with cisplatin, pemetrexed, and ipilimumab), one patient was switched from atezolizumab to nivolumab, and one patient had previously progressed on pembrolizumab.

    ‡One patient had previously progressed on nivolumab.

    • Table 3 Description of the most relevant TEAEs.

      The table includes TEAEs that were observed in three (19%) or more patients from BO-112 monotherapy cohorts 1 to 3 and in three (10%) or more patients from cohort 4, BO-112 combined with anti–PD-1.

      Adverse event
      (preferred
      term)
      All TEAEs
      n (%)
      TEAEs related to BO-112
      n (%)
      AllGrades 3–5AllGrades 3–5
      Cohorts 1–3Cohort 4Cohorts 1–3Cohort 4Cohorts 1–3Cohort 4Cohorts 1–3Cohort 4
      n = 16n = 28n = 16n = 28n = 16n = 28n = 16n = 28
      Anemia2 (12.5)5 (17.9)1 (6.3)1 (3.6)0000
      Abdominal pain1 (6.3)7 (25.0)1 (6.3)1 (3.6)0000
      Constipation2 (12.5)6 (21.4)1 (6.3)00000
      Diarrhea08 (28.6)01 (3.6)0000
      Dry mouth2 (12.5)4 (14.3)0002 (16.7)00
      Nausea4 (25.0)13 (46.4)001 (6.3)7 (25.0)00
      Vomiting2 (12.5)7 (25.0)001 (6.3)4 (14.3)00
      Asthenia4 (25.0)16 (57.1)1 (6.3)009 (32.1)00
      Chills2 (12.5)7 (25.0)002 (12.5)6 (21.4)00
      Fatigue3 (18.8)3 (10.7)002 (7.1)0
      Injection site pain1 (6.3)5 (17.9)001 (6.3)3 (10.7)00
      Pain2 (12.5)6 (21.4)01 (3.6)0000
      Pyrexia4 (25.0)21 (75.0)003 (18.8)18 (64.3)00
      Respiratory tract infection2 (12.5)4 (14.3)02 (7.1)0000
      Decreased appetite1 (6.3)9 (32.1)0004 (14.3)00
      Back pain2 (12.5)5 (17.9)1 (6.3)1 (3.6)0000
      Musculoskeletal pain04 (14.3)01 (3.6)01 (3.6)00
      Myalgia2 (12.5)7(25.0)001 (6.3)6 (21.4)00
      Neck pain03 (10.7)000000
      Tumor pain03 (10.7)01 (3.6)0000
      Dizziness1 (6.3)5 (17.9)0002 (7.1)00
      Dysgeusia04 (14.3)0002 (7.1)00
      Headache3 (18.8)6 (21.4)002 (12.5)1 (3.6)00
      Syncope04 (14.3)02 (7.1)0000
      Anxiety05 (17.9)000000
      Insomnia1 (6.3)4 (14.3)000000
      Cough04 (14.3)000000
      Dyspnea05 (17.9)000000
      Productive cough06 (21.4)000000
      Respiratory disorder04 (14.3)000000
      Pruritus06 (21.4)0003 (10.7)00

    Supplementary Materials

    • stm.sciencemag.org/cgi/content/full/12/565/eabb0391/DC1

      Fig. S1. Injected versus noninjected lesions.

      Fig. S2. Multiplex immunofluorescence staining.

      Fig. S3. Changes in apoptosis, necrosis, PD-L1, and CD8 and CD4 immunostaining after BO-112.

      Fig. S4. Heatmaps of gene expression in cohorts 1 to 3.

      Fig. S5. Unsupervised clustering of expression data in cohort 4.

      Table S1. PFS pre- and post-study in patients experiencing PD.

      Table S2. IHC findings.

      Table S3. Adjusted gene expression analysis for cohorts 1 to 3.

      Table S4. Gene expression analysis for BO-112 signature.

      Data file S1. Study protocol version 7.0.

      Data file S2. Gene expression raw data.

    • The PDF file includes:

      • Fig. S1. Injected versus noninjected lesions.
      • Fig. S2. Multiplex immunofluorescence staining.
      • Fig. S3. Changes in apoptosis, necrosis, PD-L1, and CD8 and CD4 immunostaining after BO-112.
      • Fig. S4. Heatmaps of gene expression in cohorts 1 to 3.
      • Fig. S5. Unsupervised clustering of expression data in cohort 4.
      • Table S1. PFS pre- and post-study in patients experiencing PD.
      • Table S2. IHC findings.
      • Table S3. Adjusted gene expression analysis for cohorts 1 to 3.
      • Table S4. Gene expression analysis for BO-112 signature.

      [Download PDF]

      Other Supplementary Material for this manuscript includes the following:

      • Data file S1 (.pdf format). Study protocol version 7.0.
      • Data file S2 (Microsoft Excel format). Gene expression raw data.

    Stay Connected to Science Translational Medicine

    Navigate This Article