{
  "abstract": "Background Despite the success of immune checkpoint blockade (ICB) in treating solid tumors, only a proportion of patients respond, and there is need to develop therapies to improve the quantity and quality of T cell responses. Accumulation in tumor draining lymph node and tumor of stem-like memory T cells (T SCM) or T cells expressing TCF1, a transcription factor critical in self-renewal, is important for tumor control with ICB; these tissues, however, are not easily accessible. We determined whether TSCM were present and induced in peripheral blood of cancer patients receiving invikafusp alfa (STAR0602), a first-in-class bifunctional fusion protein that simultaneously engages a nonclonal mode of T cell receptor activation with IL-2R costimulation to promote selective activation/expansion of Vβ6/Vβ10 T cells, which are prevalent across human cancers.1 Early data from START-001 (NCT05592626), an ongoing multicenter Phase 1/2 trial evaluating STAR0602 in ICB-resistant, antigen-rich tumors, demonstrated a manageable safety profile, and promising anti-tumor activity.2 Here, we characterize peripheral immune changes, including impacts on TSCM, in a subset of patients enrolled in START-001.Methods Comprehensive immune profiling was performed in peripheral blood serially collected from 10 patients in the dose escalation of START-001 (with HPV associated (n=7), esophageal (n=1), and colorectal (n=2) cancers). Complete blood counts, PBMC subsets, HPV-16-specific T cells, serum analytes, and circulating tumor DNA (ctDNA) were analyzed.Results STAR0602 expanded absolute lymphocyte and eosinophil counts, and frequencies of total CD8+ T cells. Consistent with preclinical studies, STAR0602 selectively expanded Vβ6/Vβ10 CD4+ and CD8+ T cells with central memory and effector memory phenotypes, and selectively increased T cells expressing PD-1 and Granzyme B. STAR0602 notably promoted peripheral T cell stemness, as indicated by upregulation of frequencies of T SCM, and TSCM and central and effector memory T cells expressing TCF1 in Vβ6/Vβ10 subsets. STAR0602 induced serum levels of multiple pro-inflammatory cytokines, T cell attracting chemokines, and soluble immune checkpoints. Selected patients displayed expansion of HPV-16-specific T cells, and reduction in ctDNA levels, suggestive of a tumor response to treatment.Conclusions STAR0602 induces dynamic immune activation, promoting the potent and selective activation and expansion of Vβ6/Vβ10 CD4+ and CD8+ T cells, and leads to ctDNA decrease and expansion of antigen-specific T cells. Moreover, we demonstrate that STAR0602 boosts peripheral T cells with stem-like and activated characteristics. Further studies combining STAR0602 with other immunotherapeutic agents to synergize with this peripheral burst of T cell stemness are warranted.References Hsu J, Donahue RN, Katragadda M, Lowry J, Huang W, Srinivasan K, Guntas G, Tang J, Servattalab R, Moisan J, Tsai YT, Stoop A, Palakurthi S, Chopra R, Liu K, Wherry EJ, Su Z, Gulley JL, Bayliffe A, Schlom J. A T cell receptor β chain-directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity. Sci Transl Med. 2023;15:eadi0258.Gulley JL, Sullivan RJ, Friedman CF, Sonpavde GP, Tschernia NP, Herrera M, Marabelle A, McCue S, Srinivasan K, Katragadda M, Moisan J, Bayliffe A, Chopra R, Chin K, Su Z, Liu K, Siu LL. 1470-START001: a phase 1/2 study of invikafusp alfa (STAR0602), a first-in-class TCR β chain-targeted bispecific antibody, as monotherapy in patients with antigen-rich solid tumors resistant to anti-PD(L)1: Journal for ImmunoTherapy of Cancer. 2024;12.Ethics Approval All subjects gave written informed consent. Study protocol ( NCT05592626) was approved by the NIH’s IRB, and conducted in accordance with institutional and federal guidelines.",
  "authors": [
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Yo-Ting Tsai"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Meghali Goswami"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Carolina Celades"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Christine M Minnar"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Katherine E Lothstein"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Sofia R Gameiro"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Nicholas P Tschernia"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Jennifer L Marte"
    },
    {
      "affiliations": [
        "Marengo Therapeutics, Cambridge, MA, USA"
      ],
      "name": "Andrew Bayliffe"
    },
    {
      "affiliations": [
        "Marengo Therapeutics, Cambridge, MA, USA"
      ],
      "name": "Zhen Su"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "James L Gulley"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Jeffrey Schlom"
    },
    {
      "affiliations": [
        "Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Renee N Donahue"
    }
  ],
  "title": "169 Impact of a Vβ6/Vβ10 targeting IL-2 fusion protein (invikafusp alfa) on the peripheral immunome, including stimulation of memory T cells with self-renewing properties, in patients with cancer",
  "uid": "783220ed-b4ba-596f-9739-5868d4f0be90"
}