Department of Immunology

Shivani Srivastava, Ph.D.

ASSISTANT PROFESSOR, FRED HUTCHINSON CANCER RESEARCH CENTER
AFFILIATE ASSISTANT PROFESSOR, IMMUNOLOGY

Dr. Srivastava earned a PhD in Immunology from the University of Washington in 2014. She trained as a postdoctoral fellow with Stan Riddell at the Fred Hutchinson Cancer Research Center before starting her own independent lab in the Human Biology Division of Fred Hutch in 2020. She joined the UW Department of Immunology as an Affiliate Assistant Professor in 2023.

CONTACT

ssrivas2@fredhutch.org

Fred Hutchinson Cancer Center
1100 Fairview Ave. N, S3-204
Seattle, WA 98109
Phone: 206-667-5103
Fax: 206-667-7983

RESEARCH AREAS

CAR-T cells, immunotherapy, tumor microenvironment

 

LAB

Fred Hutchinson

PUBMED

Shivani Srivastava on PubMed

RESEARCH

Immunotherapy using CAR-T cells has shown impressive efficacy in B cell malignancies but has largely been ineffective when targeting antigens on epithelial cancers, which account for 80-90 percent of all cancers. The Srivastava lab is focused on using clinically relevant animal models of human cancers to define the mechanisms limiting the activity of CAR- and TCR-engineered T cells in solid tumors and to evaluate strategies to overcome these barriers. A major focus of the lab is in understanding the principles that govern basic T cell trafficking, persistence, and activity and applying these principles to engineer more effective adoptive T cell therapies for human cancers. Our long-term goal is to work with clinical colleagues and industry partners to translate the most promising strategies to the clinic.

Transplantable and tumor xenograft models lack clinically relevant tumor microenvironments (TME), making it difficult to study the mechanisms that limit activity of transferred T cells in solid tumors. We recently adapted the KrasLSL-G12D/+p53fl/fl (KP) genetically engineered mouse (GEM) model of non-small cell lung cancer, which mimics the initiation, progression, and immunosuppressive TME of human lung cancer, to express a target for CAR-T cells, and demonstrated that this model mirrors many of the barriers to effective CAR-T cell therapy observed in patients, including poor CAR-T cell infiltration into tumors and acquired dysfunction. Using this model, we identified a novel lymphodepletion regimen that induces immunogenic tumor cell death and activates tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the TME, and increased tumor sensitivity to anti-PD-L1 checkpoint blockade and improved survival. However, the infiltrating CAR-T cells still became dysfunctional over time, suggesting that additional strategies to recruit greater numbers of T cells that retain function are needed to achieve durable efficacy. Current research in the lab is focused on:

  • Improving infiltration of engineered T cells into solid tumor masses
  • Engineering T cells to resist the development of exhaustion
  • Preserving the function of engineered T cells in immunosuppressive tumor microenvironments

PUBLICATIONS

  1. Srivastava S, Macaubas C, Deshpande C, Alexander HC, Chang S, Sun Y, Lee T, Begovich A, Mellins ED. Monocytes are resistant to apoptosis in systemic juvenile idiopathic arthritis. Clinical Immunology. 2010 Aug; 136(2): 257-68.
  2. Srivastava S, Koch MA, Pepper M, Campbell DJ. Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. Journal of Experimental Medicine, 2014 May; 211(5): 961-74.
  3. Srivastava S, Koch LK, Campbell DJ. IFNαR signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease. Journal of Immunology. 2014 Sep; 193(6): 2733-42.
  4. Srivastava S, Riddell SR. Engineering CAR-T Cells: Design Concepts. Trends in Immunology. 2015 Aug; 36(8): 494-502.
  5. Srivastava S, Riddell SR. Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to- Bedside Efficacy. Journal of Immunology. 2018 Jan; 200(2): 459-468.
  6. *Srivastava S, Salter AI, Liggitt D, Yechan-Gunja S, Sarvothama M, Cooper K, Smythe KS, Dudakov JA, Pierce RH, Rader C, Riddell SR. Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting. Cancer Cell. 2019 Mar 18; 3(35): 489-503. *Corresponding author.
  7. *Srivastava S, Furlan S, Jaeger-Ruckstuhl CA, Sarvothama M, Berger C, Smythe KS, Garrison S, Specht JM, Lee SM, Amezquita RA, Voillet V, Muhunthan V, Yechan-Gunja S, Pillai SPS, Rader C, Houghton AM, Pierce RH, Gottardo R, Maloney DG, Riddell SR. Immunogenic chemotherapy enhances recruitment of CAR-T cells to solid tumors and improves anti-tumor efficacy when combined with checkpoint blockade. Cancer Cell. 2021 Feb 8; 39(2): 193-208. *Corresponding author.
  8. Veatch J, Singhi N, Srivastava S, Szeto J, Jesernig B, Stull SM, Fitzgibbon M, Sarvothama M, Yechan-Gunja S, James S, Riddell SR. Therapeutic cancer vaccination targeting antigens and adjuvant signals to lymphoid tissues using genetically modified T cells. Journal of Clinical Investigation. 2021 Aug 16; 131(16): e144195.
  9. Nutt WS, Srivastava S. Special delivery! CAR-T cells transport RN7SL1 to the tumor microenvironment. Trends Mol Med. 2021 Nov;27(11):1019-1021.
  10. Hiatt JB, Sandborg H, Garrison SM, Arnold HU, Liao SY, Norton J, Friesen TJ, Wu F, Sutherland KD, Rienhoff HY Jr, Martins R, Houghton AM, Srivastava S, MacPherson D. Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T cell killing. Clinical Cancer Research. 2022 Oct 14; 28(20): 4551-4564. doi: 10.1158/1078-0432.CCR-22-1128.
  11. Ortiz-Espinosa S, Srivastava S. (2023). Bursting Tumor Bubbles to Improve CAR-T Cell Therapy. Cancer Research. In press. doi: 10.1158/0008-5472.CAN-23-1484.
  12. Goddard ET, Klug G*, Srivastava S*, Shabaneh TB, Grzelak CA, Shor RE, Guerrero M, Riggio AI, Veatch JR, Snyder A, Welm AL, Riddell SR, Ghajar CM. (2023). Engineered T cell immunotherapies eliminate dormant disseminated tumor cells. *These authors contributed equally. Cancer Cell. In press.
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