Discussion
tumor, DLTs, inflammation, CRS, tumors
TUMOR, INFLAMMATION, SOLID TUMORS, DYSFUNCTION, MALIGNANCIES, TUMORS
This first-in-human study has documented that SQZ-PBMC-HPV is safe and confirmed the manufacturing feasibility of autologous cell therapies using microfluidic squeezing.In devising the dosing strategy, we considered information for an approved immunomodulating, autologous cellular therapy in patients with advanced malignancies with a dose of ~0.7 × 10We observed a favorable safety profile at all dose levels. No DLTs were observed in any cohort. The majority of related TEAEs were Grade 1 or 2. There was one case of a Grade 2 CRS for a subject in the Low Dose – Single Prime cohort. In this patient, medication and supportive therapies led to their quick resolution and the CRS proved self-limiting. Interestingly, the same patient did not report any AEs following the third SQZ-PBMC-HPV administration. While this Grade 2 CRS was associated with an increase in IL-6 on the day of infusion, the overall study exhibited little variation in serum cytokines during the interval on treatment, indicative of no appreciable systemic inflammation [The hypothesized mechanism of action (MOA) for SQZ-PBMC-HPV is based upon the previously referenced studies using a murine prototype. Cytosolic loading of patient PBMCs with SLPs containing HLA-A*02-restricted E6 and E7 epitopes of HPV16 results in these cells presenting the aforementioned epitopes in an MHC-I context. Prior studies have shown this cytosolic loading of APCs is 1000 × more potent in eliciting CD8+ T cell responses via MHC-I presentation compared to the process of “cross-presentation” [Enhancement of the host cellular immune response against the HPV16+ tumor would result in increased CD8+ T cell density in the TME, as we observed in several patients (Fig. Observing pharmacodynamic features consistent with the MOA in a subset of individuals leads us to speculate about the cellular and pharmacodynamic outcomes in the other patients. As the comparative biopsies were collected 28 days into treatment, it is possible this did not provide adequate time for similar shifts to manifest, and/or requiring more treatment cycles in some participants. This may reflect the state of CD8+ T cell exhaustion and/or dysfunction that attends persistent exposure to tumor and viral antigens [A critical observation for the response experienced by patient 17 was the change in PD-L1 expression, from 2 to 100% of cells. Certainly, engagement of the PD-1 pathway would dampen the activity of tumor-infiltrating lymphocytes, the PD-1 pathway being one avenue exploited by tumors to evade the immune system [The short vein-to-vein interval (1 – 2 weeks) derives in part from the simplicity of the microfluidic squeezing process whereby product manufacturing is accomplished in < 24 h; the rest of the interval is comprised of materials transit, release testing and clinic scheduling. This is in contrast to the complexity and duration in the manufacture of other autologous adoptive cellular therapies that require genetic manipulations (In conclusion, we report safety and encouraging indications of activity for SQZ-PBMC-HPV in patients with advanced metastatic, HPV16+ solid tumors, observing increases in CD8+ TILs for several patients; the latter are strongly prognostic of improved outcomes [