On September 12, 2022 SQZ Biotechnologies Company (NYSE: SQZ), focused on unlocking the full potential of cell therapies for multiple therapeutic areas, reported that preclinical data supporting that tumor infiltrating lymphocytes (TILs) engineered with membrane-bound cytokines IL-2 (mbIL-2) and IL-12 (mbIL-12) may eliminate the need for the high-dose, systemic IL-2 and lymphodepleting preconditioning used with current TIL therapies (Press release, SQZ Biotech, SEP 12, 2022, View Source [SID1234619450]). SQZ TILs showed the ability to induce desirable cytokine signaling for more than 48 hours, which is comparable to the duration of exogenous IL-2 support in current TIL therapies. SQZ TILs also demonstrated improved killing of donor-matched tumor cells, upregulated markers associated with central memory T cells, and persistence in vivo. The data was presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022.

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"TIL therapies have shown exciting clinical results in solid tumors, but to overcome engraftment and persistence challenges they also require lymphodepletion and systemic IL-2, which are toxic to patients and prevent repeat dosing," said Jonathan Gilbert, Ph.D., Vice President of Exploratory Research at SQZ Biotechnologies. "By providing cytokine support on the surface of the cell, SQZ TILs may simultaneously eliminate the need for these toxic co-treatments and improve T cell function. Together this could potentially increase potency while also moving TILs to an outpatient procedure that allows repeat dosing and combination therapies."

The SQZ TIL platform draws from the company’s mbIL-2 and mbIL-12 constructs used in its enhanced Antigen Presenting Cell (eAPC) clinical trial. Both approaches are designed to take advantage of transient expression of membrane-bound cytokines so that potent cytokines such as IL-12 can be expressed without systemic toxicities. Additional TIL engineering with membrane-bound IL-7 (mbIL-7) and BCL-2, an anti-apoptotic factor, may further enhance the abilities of SQZ TILs to engraft without preconditioning.

Major Findings from Preclinical Research

Poster #761: Tumor Infiltrating Lymphocytes Expressing Membrane-Bound IL-2 and IL-12 Exhibit Enhanced Proliferation, Function, and Persistence Without Requiring Exogenous IL-2 Support

Cytokine Expression and Function: TILs engineered with mbIL-2 and mbIL-12 induced high levels of expression and supported >70% viability in the absence of external cytokine support for 5 days, a time greater than IL-2 is typically dosed in the clinic after TIL infusion. The membrane-bound cytokines produced an almost 4-fold expansion in vitro, which was comparable to unmodified TILs cultured in IL-2 containing media
Tumor Cell Killing: TILs from primary solid tumors engineered with mbIL-2 and mbIL-12 and subsequently cultured with donor-matched tumor cell lines showed 3.5-fold higher IFN-y release than the current clinical standard of unmodified TILs with exogenous IL-2, as well as increased tumor killing as measured by staining of apoptotic cells
Memory T Cell Reprogramming: TILs engineered to express mbIL-2 and mbIL-12 upregulated CD62L, a classical marker of central memory T cells (>80% positive, vs <20% positive for unmodified TILs at day 6). CD62L remains upregulated even after cytokine expression has diminished, suggesting a potential reprogramming of the TILs to a more memory-like state, which could positively impact T cell survival and clinical benefit
In Vivo Survival and Phenotype: mbIL-2 and mbIL-2/12 TILs adoptively transferred into a mouse model each showed more than 200% greater cell persistence in vivo as compared to unmodified TILs, and mbIL-12 drove a 3.5-fold enrichment in CD62L expression in vivo out to at least day 5 post-transfer
Promising Targets: TILs engineered with mbIL-7 and BCL2, which can support cell survival, demonstrated a strong advantage in the absence of exogenous cytokine support and could serve as potential future TIL enhancers