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Abstract
Background Cluster of differentiation 70 (CD70) is a type II transmembrane protein belonging to the tumor necrosis factor superfamily.1 In normal tissues, CD70 is transiently expressed in activated lymphocytes, including B, T, NK cells, and mature dendritic cells.2 CD70 is aberrantly expressed in solid and hematologic cancers (figure 1) and is implicated in enhanced growth, metastasis, and immune evasion and suppression.2–5 In clear cell renal cell carcinoma (ccRCC), CD70 expression is increased in the tumor microenvironment and on malignant cells.6 Despite advancements in therapies for patients with metastatic RCC, the 5-year survival rate is 15% and an unmet need remains.7
ADI-270 is an investigational, allogeneic, CD70-targeting (CD27 receptor-based) Vδ1 γδ chimeric antigen receptor (CAR) T cell therapy expressing a dominant negative form of the TGFβ receptor II to provide resistance against the immunosuppressive tumor microenvironment.8 γδ T cells possess innate and adaptive immune response functions and a natural role in immune surveillance and anti-tumor immunity, including the ability to home to tissues and survive in hypoxic conditions.9–11 γδ T cells are ideal for an allogeneic cell therapy as their TCR recognizes MHC-independent antigens, thereby avoiding the risk of graft versus host disease without the need for gene editing12 ADI-270 has demonstrated potent preclinical activity against CD70 expressing tumors and superior activity to αβ T cell-derived benchmarks currently in phase I clinical development (figures 2 - 4).
Methods ADI-202427001 is a phase 1/2 open-label, dose-escalation and -expansion study evaluating ADI-270 in adult patients with relapsed/refractory ccRCC. Key inclusion criteria include confirmed diagnosis of relapsed/refractory advanced/metastatic ccRCC, previous treatment with an immune checkpoint inhibitor and a VEGF inhibitor, and Karnofsky performance status >= 70. Key exclusion criteria include previous CD70 targeting treatment and autoimmune disease requiring ongoing systemic immunosuppressive therapy. The objectives of phase 1 include characterizing the safety and tolerability of ADI-270, identifying the recommended phase 2 dose (RP2D), and assessing cellular kinetics (CK), immunogenicity, pharmacodynamics (PD), and anti-tumor activity. The objectives of phase 2 include characterizing the anti-tumor activity, safety, immunogenicity, and PD profile of ADI-270 at the RP2D (see figure 5). The available safety, efficacy, CK, and PD data from Phase 1 will be used to determine the RP2D. Responses will be evaluated per the RECIST 1.1 criteria.13 Additional efficacy analyses include duration of response, progression-free, and overall survival. All patients will give informed consent.
AcknowledgementsDrs Beckermann, Rini, Garmezy, and Pal contributed equally to the development of this abstract.
Trial Registration The trial registration number is NCT06480565.
References
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Ethics Approval This is a trial in progress, the institutional review boards of all active sites will provide approval prior to patient enrollment, all patients will provide informed consent. At the time of submission of this abstract, no patients have enrolled on the study.
CD70 is expressed on multiple solid and hematological cancers with limited expression in normal tissues. A. H-Score across hundreds of patient samples from hematologic and solid tumors stained for CD70. B. CD70 IHC images (10x objective) showing absence of CD70 staining on normal tissues; rare CD70+ staining on immune cells (arrows)
In vitro cytotoxicity of ADI-270 against multiple human tumor cell lines with varying CD70 expression A. CD70 by flow cytometry. B. ADI-270 cytotoxicity in hematologic/solid tumors with variable CD70 expression, E:T ratio 1:1. Cytotoxicity Index=total near infrared object area (mm^2/well) post stimulation/time 0; mean±std deviation of biologic triplicates
ADI-270 retained potent activity in the context of CD70-low tumors compared to clinically relevant CD70-targeting αβ CAR T cell benchmarks. In cytotoxicity assays against RCC cell lines, ADI-270 retains similar activity against CD70-high A498 cells and CD70-low ACHN cells while αβ CAR T cell benchmarks show significantly reduced activity against ACHN
ADI-270 demonstrated potency and sustained systemic anti-tumor activity in A498 ccRCC xenograft. Single ADI-270 dose day 23 post implantation (n=5/group) with complete tumor control at both levels. Same mice had A498 tumors implanted to opposite flank day 18 post-ADI-270 with inhibited growth of new tumors demonstrating ability to mount 2nd response
Study ADI-202427001 schema
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