Preclinical Work on Red Blood Cell-Based Therapies in HPV-Positive Solid Tumors Provides Rationale for Clinical Trials in Humans – Cancer Therapy…

A new technology for producingactivated antigen carrier cells (AACs) for cancer immunotherapy was presentedby the biotechnology company SQZ Biotech at the Society for Immunotherapy ofCancer (SITC) meeting in Maryland in November 2019.1

The innovative technique uses amicrofluidics platform to introduce antigen and adjuvant to red blood cells(RBCs), which are then introduced to the patient and engulfed by antigen-presentingcells in order to generate a T-cell response. The company presented preclinicaldata at SITC, detailing the steps of the new production technique and showingdata from preliminary mouse model work.

SQZ chose to first test thetherapy on the TC-1 tumor model of human papillomavirus (HPV)-positive cancers,a common target, as the E6 and E7 HPV tumor antigens are unique to tumors andabsent on healthy cells. The preliminary data show that in mice, the engineeredAACs are briskly taken up and engulfed by macrophages and dendritic cells,resulting in clearance from the blood within 60 minutes.

When you inject the engineeredcells in mice, they get taken up very quickly within the phagocytic cellswithin the hour. We see powerful CD8 T-cell responses and CD4 T-cell responses.These CD8 responses subsequently infiltrate the tumor and drive a very strongtumor regression, said Armon Sharei, PhD, SQZ CEO and cofounder.

The team implanted a tumor cellline in mice before treating them with engineered AACs after 10 days. Analysis of the tumor-infiltratinglymphocytes in these mice showed that approximately 70% of them were specificfor the antigen introduced by the engineered AACs.

IfI read the data correctly, what they report is that in that experiment, thevast majority of the T cells in the tumor were specific for the peptide in thetumor cells. This is remarkable, as this is evidence for a very specific effect,said Christian Ottensmeier, MD, PhD, professor of experimental medicine at theUniversity of Southampton in the U.K.

The AAC treatment also increasedsurvival and reduced tumor volume in some of the tumor-engrafted mice but theresults were perhaps a little underwhelming considering the high specificity ofthe reported T-cell response.

Onlyabout 50% of the mice survived; that is less than I would have expected forsuch an impressive T-cell response, said Dr Ottensmeier. The experiments needto be expanded upon to further investigate this discrepancy. Why are the Tcells only tackling the tumor effectively in 50% of the mice?

The work is only preliminary, but several questions will be addressed in a planned clinical trial, adding to a similar, ongoing trial using peripheral blood mononuclear cells targeting HPV-positive solid tumors (ClinicalTrials.gov Identifier: NCT04084951). On January 30, 2020, SQZ announced that the first patient in its phase 1 trial of SQZ-PBMC-HPV had been dosed. It is the first trial advancing into the clinic that was part of the 2018 SQZ-Roche collaboration, which will focus on antigen-presenting cells in oncology.2

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Preclinical Work on Red Blood Cell-Based Therapies in HPV-Positive Solid Tumors Provides Rationale for Clinical Trials in Humans - Cancer Therapy...