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Poster session 14

761P - Tumor infiltrating lymphocytes expressing membrane-bound IL-2 and IL-12 exhibit enhanced proliferation, function, and persistence without requiring exogenous IL-2 support

Date

10 Sep 2022

Session

Poster session 14

Topics

Tumour Immunology;  Cell-Based Therapy;  Immunotherapy

Tumour Site

Ovarian Cancer;  Melanoma;  Non-Small Cell Lung Cancer

Presenters

Rebecca J. Silver

Citation

Annals of Oncology (2022) 33 (suppl_7): S331-S355. 10.1016/annonc/annonc1058

Authors

R.J. Silver1, M. Silva1, M.F. Maloney2, A.A. Brate2, N. El-Sayes2, E.I. Ozay2, D. Parwanda1, C. Bartlett1, A. Sharei2, S.M. Loughhead2, J. Gilbert1, D.T. Bridgen1

Author affiliations

  • 1 Exploratory, SQZ Biotechnologies, 02472 - Watertown/US
  • 2 R&d, SQZ Biotechnologies, 02472 - Watertown/US
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Abstract 761P

Background

Tumor Infiltrating Lymphocyte (TIL) therapies have shown significant solid tumor activity in patients, but many current TIL regimens require lymphodepletion and high-dose IL-2 after cell infusion to support TIL persistence and clinical activity. Removing these requirements that cause systemic toxicity while maintaining or improving TIL product functionality by ex vivo engineering of the TIL product with transient expression of mRNA could dramatically improve the patient experience, expand the eligible patient population, and potentially allow repeat dosing.

Methods

mRNAs encoding for membrane-bound (mb) IL-2 or IL-12 were delivered directly to the cytosol of TILs expanded from either melanoma, lung, or ovarian solid tumors using the microfluidic Cell Squeeze® technology. After mRNA delivery, TILs were cultured in vitro without exogenous IL-2 or adoptively transferred into NOD scid gamma (NSG) mice, and TIL persistence in the blood was characterized by flow cytometry.

Results

We demonstrated that mbIL-2 and mbIL-12 support TIL expansion in vitro at rates comparable to control cells incubated with a high concentration of cytokines for 2-3 days. Furthermore, we identified mbIL-12-dependent upregulation of L-selectin (CD62L), a surface protein associated with central memory T cells (TCM), which remains upregulated beyond the expression window of mbIL-12 both in vitro and in vivo. Lastly, we show mbIL-2/12 TILs can expand in an NSG mouse and persist comparable to mice that received exogenous IL-2.

Conclusions

Through microfluidic Cell Squeeze® delivery of mRNAs, we engineered TILs with membrane-bound cytokines that proliferate, persist, and upregulate markers of TCM, a self-renewing T cell sub-type that is known to confer superior antitumor immunity. Enhanced TILs can potentially alleviate current requirements for toxic high-dose IL-2 support and lymphodepleting preconditioning regimens.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

SQZ Biotechnologies Company.

Disclosure

R.J. Silver: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. M. Silva: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. M.F. Maloney: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. E.I. Ozay: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. D. Parwanda: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. C. Bartlett: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. A. Sharei: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. S.M. Loughhead: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. J. Gilbert: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies. D.T. Bridgen: Non-Financial Interests, Personal and Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal and Institutional, Stocks/Shares: SQZ Biotechnologies.

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