Just thought I'd clarify my thesis on current $PDSB trial: New research has made it clear that interferon-y release by T cells in TME is critical for anti-tumor immune response. To achieve this you need to 1. Get T-cells to the tumor and 2. Stimulate T-cell activity at site 1/n

of tumor. Respective readouts for hitting these goalposts are 1. Change in # of T-cells infiltrating tumor post-treatment relative to pre-treatment and 2. Increase in T-cell clonality, or how many T-cells targeting the same antigen proportionally exist at the tumor. $PDSB 2/n

started a trial in June for PDS101+NHS-IL12+Bintrafusp-alpha for advanced HPV malignancies. PDS101, a T-cell stimulating vaccine, generates T-cells that are reactive against HPV antigens, and has already been shown to increase T-cell infiltration of HPV+ tumors as well as 3/n

generate a 60-80% response rate between 1-3 months as a monotherapy. NHS-IL12 is an antibody targeted to necrotic DNA, which is present in tumor cells w/ high apoptotic rates. It has an IL-12 payload, which stimulates T-cells to produce interferon-y. Bintrafusp-alpha 4/n

is an antibody that blocks PDL-1, as well as carries the TGFBR2 extracellular domain, which 'traps' TGFB, a suppressor of CD8+ T-cell activity. Thus in combo, these 3 agents 1. Generate tumor-reactive T-cells that find tumor and 2. Provide signals at the tumor that help 5/n

T-cells to overcome the immunosuppressive environment. Does this strategy actually work? In mice TC-1 model, the triple combo both synergistically generated T-cell occupancy of tumor, as well as clonality of said T-cells. This means that T-cells are not only getting to tumor 6/n

but also expanding at tumor into clones that are reactive against HPV. This is critical, as it shows that T-cells are overcoming suppression and are highly active. Perhaps not surprisingly, the triple combo showed synergistic reduction of tumor size as well. Furthermore 7/n

NHS-IL12 and Bintrafusp-alpha have shown anti-tumor activity and safety as monotherapies, w/ the latter achieving almost a ~40% ORR in HNSCC which is superior to ~20% ORR achieved by Opdivo alone. While safety could be a concern in combo, NHS-IL12 and PDL1i have already 8/n

shown safety as combo in clinic, and PDS101 generates highly specific anti-HPV T-cells. Basically this combo seems to rationally address limitations of PDL1i by itself, and thus could greatly increase response rates imo if safe. Read-out June 2021, sp irrelevant until then imo.