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Abstract
Background T cell therapies offer a promising, targeted approach for patients with relapsed/refractory (r/r) solid tumors. Patient-derived multi tumor-associated antigen-specific T cell (TAA-T) products targeting WT1, PRAME, and survivin have been safely administered to patients with r/r disease with disease stabilization but no objective clinical responses. Lymphodepleting chemotherapy (LD) prior to therapy with chimeric antigen receptor (CAR) T cell and tumor-infiltrating lymphocyte (TIL) products has been necessary for efficacy. We hypothesized that TAA-T treatment is enhanced using LD pre TAA-T by promoting homeostatic lymphoproliferation, altering the tumor microenvironment, and increasing TAA-T persistence in vivo.
Methods TAA-T products were administered after LD (cyclophosphamide and fludarabine) at recommended dose level (4 x 107/m2/dose) with repeat doses without LD in the absence of disease progression. Clinical and immunobiological studies were performed using TCR sequencing, flow cytometry and IFNy ELISpot assays to assess immunologic and anti-tumor responses.
Results TAA-T products were generated from 9 patients (age range 5–38 years) with r/r solid tumors with a median of 2 (range 1–8) infusions per patient without therapy-related severe adverse events. 7 of 9 patients achieved disease stabilization for a median of 3+ months (range 1.4–23.4+) with no objective clinical responses (figure 1). Compared to patients who received TAA-T without LD, there was greater expansion of TAA-T product-derived TCR clonotypes in vivo (figure 2). Conversely, patients who received TAA-T products following LD demonstrated less antigen spreading with a reduced IFNy response (mean pre-infusion 6 IFNy SFC/1e5 cells, range 0–61, and mean post-infusion 42 IFNy SFC/1e5 cells, range 3–132) compared to patients who received TAA-T products alone (mean pre-infusion 21 IFNy SFC/1e5 cells, range 0–82, and mean post-infusion 66 IFNy SFC/1e5 cells, range 0–270) (figure 3). Investigation of circulating cytokines in patients post LD and TAA-T product infusion showed elevated levels of IL-8 in patients with disease progression.
Conclusions LD with TAA-T was well-tolerated with enhanced TAA-T expansion in vivo. However, the blunted antigen spreading response as well as product-related factors could explain the lack of objective clinical responses. As seen in previous patients, elevated IL-8 was correlated with disease progression representing a potential biomarker for future study. Other future directions will seek to investigate strategies to enhance product potency including using third-party, healthy donor derived, partially HLA-matched TAA-T as an off-the-shelf therapy (NCT05238792) and gene modification to sink IL-8 from the tumor microenvironment.
Acknowledgements We acknowledge the support of the Department of Defense Peer Reviewed Cancer Research Program Career Development Award.
Ethics Approval Informed consent was obtained from patients meeting standard eligibility requirements including performance status and organ function parameters prior to cell procurement and TAA-T infusion. This study was approved by the US Food and Drug Administration (IND 16135) and Children’s National Hospital Institutional Review Board (NCT02789228).
(A) Patients received multiple TAA-T infusions safely on dose escalation phase (B) Patients with WT on expansion cohort received TAA-T infusions safely with LD on dose level 3. Patients received median 2 (range1–8) infusions per patient. OS: osteosarcoma; WT: Wilms tumor; NB: neuroblastoma; STS; soft tissue sarcoma; ES: Ewing sarcoma; RMS: rhabdomyososarcoma; Data censored at January 1, 2023
Greater expansion of product-derived clonotypes in a patient following LD prior to TAA-T administration (right) compared to a patient who received TAA-T product without LD (left), supporting T-cell persistence, expansion
Antigen spreading in patients without LD (A) and preserved with LD but blunted (B)
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