T Cell Immunotherapy of Infection Disease and Cancer

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Scott Weber, Microbiology and Molecular Biology

1) Project Summary

This project was focused on improving the immune response to infectious disease and cancer. We have engineered T cell receptors with 1000-fold increase in affinity and will characterize their value as diagnostics and therapeutics. In addition, we examined changes in T cell function due to the co-receptor CD5. We also examined how T cell responses to infection are dependent upon metabolic and epigenetic regulation.

A) Evaluation of of how well the academic objectives were met:

We were able to meet our goals of better understanding the T cell response to cancer as evidence by the published 6 papers describing our work.

B) Evaluation of the mentoring environment

We have met our goals of high-quality mentoring for a number of students. On our 6 publications there are 23 student authors and on our 37 student poster presentations there are 135 student authors.

C) List of students who participated and academic deliverables

See 6 publications and 37 posters with the students listed below

D) Description of the results

While the details are found in the published papers listed, we have successfully found that CD5 plays a key role in regulating T cell responses and these findings are being applied in the development of novel cancer immunotherapies.

E) Description of how the budget was spent

Graduate student wages – $7,500

Undergraduate student wages $2,500

Supplies (antibodies, flow cytometry, cell culture media, metabolism kits) $10,000

2) Published papers that the MEG supported

*= BYU Undergraduate † = BYU Graduate Student

  1. †Townsend MH, *Anderson MD, †Weagel EG, †Velazquez EJ, *Peck CJ, Weber KS, Robison RA, and O’Neill KL. (2017) Non-Small Cell Lung Cancer Cell lines A549 and NCI-H460 Express HPRT on the Plasma Membrane. OncoTargets and Therapy. Mar 30, 2017:10 1921-1932
  2. †Freitas CMT, *Hamblin GJ, *Raymond CM and Weber KS. (2017) Naive T helper cell with high CD5 levels has improved calcium mobilization. PLoS ONE. May 31; 12(5): e0178799.
  3. †Weagel EG, *Meng W, †Townsend MH, †Velazquez-Espinoza E, *Brog RA, Weber KS, Robison RA, O’Neill KL. (2017) Biomarker analysis and clinical relevance of thymidine kinase 1 on the cell membrane of Burkitt’s lymphoma and acute lymphoblastic leukemia. OncoTargets and Therapy. September 6, 2017. 10:4355-4367
  4. †Freitas CMT, †Johnson DK, and Weber KS. (2018) T cell calcium signaling regulation by the CD5 coreceptor. International Journal of Molecular Sciences. 19(5), 1295; doi: 10.3390/ijms19051295
  5. †Weagel EG, *Burrup W, *Kovtun R, †Velazquez EJ, *Felsted AM, †Townsend MH, *Ence ZE, *Suh E, Piccolo SR, Weber KS, Robison RA, and O’Neill KL. (2018) Membrane expression of thymidine kinase 1 and potential clinical relevance in lung, breast, and colorectal malignancies. Cancer Cell International. 18:135 doi.org/10.1186/s12935-018-0633-9
  6. †Freitas CF, *Burrell HR, *Valdoz JC, *Hamblin GJ, *Raymond CM, *Cox TD, †Johnson DK, *Anderson JL, Weber KS, and Bridgewater LC. The nuclear variant of bone morphogenetic protein 2 (nBMP2) is expressed in macrophages and alters intracellular calcium mobilization. Scientific Reports.

3) Student presentations supported by MEG

*= BYU Undergraduate † = BYU Graduate Student W = Oral presentation S =Poster presentation

  1. HPRT Overexpression May Contribute to the Immunosuppressive Tumor Microenvironment. Townsend MH†, Ewell ZD*, Freitas CMT†, Larsen DJ*, Lawrence EL†, Bennion KB*, Piccolo SR, Weber KS, Robison RA, and O’Neill KL. American Association for Cancer Research Annual Meeting. March 29-April 3 2019 Atlanta, GA
  2. Johnson R*, Hancock J*, Vaden K†, and Weber KS. Development of anti-thymidine kinase 1 antibody (WHEELZ) as a potential cancer immunotherapy. Utah Conference on Undergraduate Research. February 22nd, 2019. Ogden Utah
  3. Teames C* and Weber KS. Role of CD5 on T regulatory function. Utah Conference on Undergraduate Research. February 22nd, 2019. Ogden Utah
  4. Magoffin W*, Johnson D†, and Weber KS. Characterizing the effectiveness of a novel helper T cell chimeric antigen receptor immunotherapy. Utah Conference on Undergraduate Research February 22nd, 2019. Ogden Utah
  5. Freitas C†, Cox T*, Dunne A*, and Weber KS. CD5 co-receptor plays a role in T cell metabolism. Midwinter Immunology Conference. Jan 26-29, 2019. Asilomar CA
  6. HPRT impact on immune regulation influences the tumor microenvironment. Townsend MH†, Bitter EK*, Larsen D*, Freitas CMT†, Piccolo SR, Weber KS, Robison RA, O’Neill KL. Midwinter Immunology Conference. Jan 26-29, 2019. Asilomar CA
  7. Freitas CM†WS, Cox TD*, Johnson DK†, and Weber KS. CD5 expression influences T cell metabolism and mice behavior. The American Association of Immunologists Annual Meeting. May 4-8th Austin TX
  8. Townsend MH†S, Olson E*, Weagel EG†, Velazquez EJ†, Felsted AM*, Burrup WS*, Weber KS, Robison RA, and O’Neill KL. HPRT: A biomarker and potential target for detection and treatment of colorectal cancers. American Association for Cancer Research Annual Meeting. April 14-18th 2018 Chicago IL
  9. Velazquez EJ†S, Lattin JE*, Brindley TD*, Reinstein ZZ*, Chu R*, Liu L*, Weagel EG†, Townsend MH†, Whitley KV†, Lawrence EL†, Garcia BT*, Weber KS, Robison RA, and O’Neill KL. Macrophage toll-like receptor-chimeric antigen receptors (MOTO-CARs) as a novel adoptive cell therapy for the treatment of solid malignancies. American Association for Cancer Research Annual Meeting. April 14-18th Chicago IL
  10. Townsend MH†S, Clay T*, Felsted AM*, Burrup WS*, Weagel EG†, Velazquez EJ†, Weber KS, Robison RA, and O’Neill KL. Evaluating surface expression of the nucleotide salvage pathway enzyme HPRT on colorectal cancer cells. American Association for Cancer Research Annual Meeting. April 14-18th Chicago IL
  11. Whitley KV†S, Velazquez EJ†, Bennion KB*, Kingery BM*, Weber KS, and O’Neill KL. “Wheelz”: A novel engineered human antibody for possible CAR T-cell therapy. American Association for Cancer Research Annual Meeting. April 14-18th Chicago IL
  12. Cox TD*W, Freitas CM†, Yorgason JT, Franson JJ†, Bridgewater LC, Steffensen SC, and Weber KS. CD5 deficient mice exhibit altered cognitive function in behavioral studies. Tri-Branch American Society of Microbiology Meeting. April 7th, 2018. Durango CO

–Winner of best undergraduate oral presentation award

  1. Johnson DK†W, Freitas CM†, Hancock JC*, Tueller JA*, Myers SJ*, Hamblin GJ* and Weber KS. CD5 expression influences helper T cell metabolic state. Tri-Branch American Society of Microbiology Meeting. April 7th, 2018. Durango CO
  2. Freitas CM†W, Cox TD*, Johnson DK†, Franson JJ†, Bridgewater LC, and Weber KS. Role of CD5 expression on T cell metabolism. Tri-Branch American Society of Microbiology Meeting. April 7th, 2018. Durango CO
  3. Wynn AG, Garland KG, Kener KB, Weber KS, Bikman BT, Hancock CR, Tessem JS. High Fat Fed Nr4a1 Knock Out Mouse has Significant Modulation of Mitochondrial Respiration Across Various Tissues. The FASEB Journal. April 2018. 32:1
  4. Bennion KB*S, Whitley KV†, Velazquez EJ†, Kingery BM*, Weber KS, and O’Neill KL. “Wheelz”: A novel engineered human antibody for possible CAR T-cell therapy. BYU College of Life Science Poster Competition. March 29th, 2018. Provo Utah
  5. Cox TD*S, Freitas CM†, Yorgason JT, Franson JJ†, Bridgewater LC, Steffensen SC, and Weber KS. CD5 deficient mice exhibit altered cognitive function in behavioral studies. BYU College of Life Science Poster Competition. March 29th, 2018. Provo Utah
  6. Garland K*S, Kener K*, Hancock J*, Freitas CMT†, Bickman B, Hancock C, Weber KS, and Tessem J. The effects of Nr4a1 full-body knockout in mice. Utah Conference on Undergraduate Research. February 9th, 2018. Cedar City Utah
  7. Cox TD*WS, Freitas CM†, Yorgason JT, Franson JJ†, Bridgewater LC, Steffensen SC, and Weber KS. CD5 deficient mice exhibit altered cognitive function in behavioral studies. Autumn Immunology Conference 46th Annual Meeting. November 17-20th Chicago Illinois
  8. Tueller JA*WS, Whitley KV†, Velazquez EJ†, Weagel EG†, O’Neill KL, and Weber KS. Generation and metabolic characterization of TK-1 specific 2nd and 3rd generation CAR vectors. Autumn Immunology Conference 46th Annual Meeting. November 17-20th Chicago Illinois
  9. Johnson DK†WS, Freitas CM†, Hancock JC*, Tueller JA*, Myers SJ*, Hamblin GJ* and Weber KS. CD5 expression influences helper T cell metabolic state. Autumn Immunology Conference 46th Annual Meeting. November 17-20th Chicago Illinois
  10. Johnson D†W and Weber KS. T cell receptors specific for a naturally occurring Listeria monocytogenes epitope engineered in vitro for high affinity. American Society for Microbiology Intermountain Branch Meeting. April 15th Ogden Utah
  11. Freitas CT†W, Hamblin GJ*, Larsen CM*, Weber KS. Naive Helper T Cells with high CD5 expression have increased calcium signaling. American Society for Microbiology Intermountain Branch Meeting. April 15th Ogden Utah
  12. Vaden K†W, Hancock III JC*, Weber KS. Determining the Optimal TCR:pepMHC Affinity for CD4+ T cell Primary and Memory Response. American Society for Microbiology Intermountain Branch Meeting. April 15th Ogden Utah
  13. ΔVelazquez-Espinoza E†S, Ewell ZD*, Lattin JE*, Vaden K†, Townsend MH†, Weagel EG†, Weber KS, Robison RA, and O’Neill KL. A pre-clinical study of chimeric antigen receptor (CAR) T cells targeting Thymidine Kinase 1 (TK1) in lung cancer cell lines. American Society for Microbiology Intermountain Branch Meeting. April 15th Ogden Utah.

 Δ Poster won first place in the competition.

  1. Townsend MH†S, Burrup W*, Weagel EG†, Felsted A*, Anderson MD*, Velazquez-Espinoza E†, Weber KS, Robison RA, O’Neill KL. HPRT: Could it be used as a biomarker for future immunotherapies? Undergraduate student caucus and poster competition. American Association for Cancer Research April 1-5th Washington DC
  2. Velazquez-Espinoza E†S, Vaden K†, Townsend MH†, Weagel EG†, Weber KS, Robison RA, and O’Neill KL. Development of a TK1 specific chimeric antigen receptor T cell for the treatment of non-small-cell lung cancer. American Association for Cancer Research. April 1-5th Washington DC
  3. Weagel EG†S, Townsend MH†, Anderson MD*, Velazquez EJ†, Weber KS, Robison RA, O’Neill KL. Unusual expression of HPRT on the surface of the colorectal cancer cell lines HT29 and SW620. American Association for Cancer Research. April 1-5th Washington DC
  4. Tueller J*S, Vaden K†, Weber KS. Engineering a Cancer-Specific Third Generation CAR Immunotherapy. 11th Annual Utah Conference on Undergraduate Research. February 17, 2017. Orem Ut
  5. Vaden K†S, Hancock III JC*, Weber KS. Determining the Optimal TCR:pepMHC Affinity for CD4+ T cell Primary and Memory Response. Midwinter Immunology Conference. Jan 28-31, 2017. Asilomar CA
  6. Freitas CT†S, Hamblin GJ*, Larsen CM*, Weber KS. Naive Helper T Cells with high CD5 expression have increased calcium signaling. Midwinter Immunology Conference. Jan 28-31, 2017. Asilomar CA.
  7. Velazquez-Espinoza E†S, Vaden K†, Townsend MH†, Weagel EG†, Weber KS, Robison RA, and O’Neill KL. Chimeric Antigen Receptor (CARs) for Thymidine Kinase 1 (TK1): A novel immunotherapy approach to fight cancer. Biomedical Engineering West Regional Conference. January 19-20th Provo Utah
  8. Johnson DJ† and Weber KSW. Role of affinity for antigen and self in T cell activation and memory generation. LDS Life Science Research Symposium. July 20-22nd Lehi Utah
  9. Crandall J*S, Vaden K†, O’Neill K, and Weber KS. Sequencing an antibody specific for an epitope overexpressed on cancer cells. 10th Annual Utah Conference on Undergraduate Research. February 19th Salt Lake City. Utah
  10. Hamblin G*S, Freitas C†, Steadman N*, Williams K*, and Weber KS. Calcium Signaling in Primary and Secondary Responses of Listeria specific T helper cells. 10th Annual Utah Conference on Undergraduate Research. February 19th Salt Lake City. Utah
  11. Myers S*S, Johnson D†, Anderson B*, Ehlers K*, Orton T*, Ballard B*, Persaud S, Weber KS. Engineering High Affinity Class II TCRs Specific for Listeria monocytogenes. 10th Annual Utah Conference on Undergraduate Research. February 19th Salt Lake City. Utah
  12. Vaden K†S and Weber KS. Determining the optimal TCR:pMHC avidity for CD4+ T cell memory generation. Midwinter Conference of Immunologists. January 23-26 2016. Asilomar CA