Focus Areas

The research of Saad J. Kenderian, M.B., Ch.B., and his team centers on the development and optimization of novel-engineered T cell therapy approaches to treat cancer. His team collaborates with other teams and centers within Mayo Clinic and has several research efforts in early-phase clinical trials.

Research platforms of the T Cell Engineering Lab include:

• Improving CAR-T cell efficacy. The lab is investigating several strategies to enhance the activity of CAR-T cells. These include secondary modification of CAR-T cells and combination strategies with monoclonal antibodies, small molecules, peptides and other immunotherapeutic strategies.
• Preventing CAR-T cell toxicities. The lab is exploring methods to reduce severe toxicities that are associated with CAR-T cell therapy, including cytokine release syndrome and neurotoxicity. Current strategies include secondary modification of CAR-T cells and combination strategies with monoclonal antibodies or small molecule inhibitors.
• Expanding engineered cellular therapy. The lab is investigating applying the principles of CAR-T cell therapy to other cancers and autoimmune disease.
• Producing CAR-T cells more efficiently. Two strategies are being researched in the lab: generating CAR-T cells in vivo (bypassing the need for ex vivo expansion) and generating nonviral CAR-T cells.
• A platform for in-house production of CAR-T cells for clinical trials.

Improving CAR-T cell therapeutic efficacy

Despite the success and FDA approval of CAR-T cell therapy in hematological malignancies, the durable response rates are low, and most patients relapse within the first two years after CAR-T cell therapy. Mechanisms of failure of CAR-T cell therapy include tumor escape, inhibition of T cells by tumor microenvironment, and intrinsic T cell defects.

Using viral and nonviral constructs, synthetic biology tools, mouse models, and patient samples from CAR-T cell clinical trials, the laboratory has identified key genes of T cell resistance and different components of the tumor microenvironment that induce CAR-T cell suppression. The laboratory team is developing strategies to overcome this resistance.

Team

• Ismail Can, Ph.D.
• Michelle J. Cox, Ph.D., M.S.
• Claudia Manriquez Roman, Ph.D., M.S.
• Leo Sakemura, M.D., Ph.D.
• Carli M. Stewart
• Kun Yun

Collaborators

• Andrew D. Badley, M.D.
• Neil E. Kay, M.D.

Relevant published highlights

• Cox M, Lucien F, Sakemura R, Boysen JC, Kim Y, Horvei P, Manriquez Roman C, Hansen M, Tapper EE, Siegler EL, Forsman C, Crotts SB, Schick KJ, Hefazi M, Ruff MW, Can I, Adada M, Bezerra E, Kankeu Fonkoua L, Nevala WK, Braggio E, Ding W, Parikh SA, Kay NE, Kenderian SS. Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia. Molecular Therapy. 2020; doi:10.1016/j.ymthe.2020.12.033.
• Sakemura R, Cox MJ, Hansen MJ, Hefazi M, Manriquez Roman C, Schick KJ, Tapper EE, Roman Moreno P, Ruff MW, Walters DK, Parikh SA, Kay NE, Kenderian SS. Targeting cancer associated fibroblasts in the bone marrow prevents resistance to chimeric antigen receptor T cell therapy in multiple myeloma. Blood. 2019; doi:10.1182/blood-2019-123277.
• Sterner RM, Kenderian SS. Myeloid cell and cytokine interactions with chimeric antigen receptor-T-cell therapy: Implication for future therapies. Current Opinion in Hematology. 2020; doi:10.1097/MOH.0000000000000559.

Preventing CAR-T cell toxicities

The main limiting toxicities after CAR-T cell therapy include developing cytokine release syndrome (CRS) and neurotoxicity, which are life-threatening and can be fatal. The development of CRS is related to rapid expansion of T cells and subsequent cytokine release and is typically treated with interleukin-6 (IL-6) receptor blockade and steroids. However, the use of steroids is associated with suppression of CAR-T cells and inhibition of their functions. The mechanisms of neurotoxicity are not well understood, and no effective treatment is available. Steroids are used routinely in the clinic, but their efficacy in reducing the severity of neurotoxicity is unclear.

The laboratory team has used preclinical models and patient samples to gain insights into mechanisms of neurotoxicity after CAR-T cell therapy, and to develop strategies to prevent and mitigate these toxicities.

Team

• Michelle J. Cox, Ph.D., M.S.
• Leo Sakemura, M.D., Ph.D.
• Liz L. Siegler, Ph.D., M.S.

Collaborators

• Andrew D. Badley, M.D.
• Aaron J. Johnson, Ph.D.
• Zelalem Temesgen, M.D.

Relevant published highlights

• Sterner R, Sakemura R, Cox M, Yang N, Khadka R, Forsman C, Hansen M, Jin F, Ayasoufi K, Hefazi M, Schick K, Walters D, Ahmed O, Chappell D, Sahmoud T, Durrant C, Nevala W, Patnaik M, Pease L, Hedin K, Kay N, Johnson A, Kenderian S. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019; doi:10.1182/blood-2018-10-881722.
• Kenderian SS, Oluwole OO, McCarthy PL, Reshef R, Shiraz P, Ahmed O, Le Gall J, Nahas M, Tang L, Neelapu SS. ZUMA-19: A phase 1/2 multicenter study of lenzilumab use with axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with relapsed or refractory large B cell lymphoma (R/R LBCL). Blood. 2020; doi:10.1182/blood-2020-135988.
• Ruff MW, Siegler EL, Kenderian SS. A concise review of neurologic complications associated with chimeric antigen receptor T-cell immunotherapy. Neurologic Clinics. 2020; doi:10.1016/j.ncl.2020.08.001.
• Siegler EL, Kenderian SS. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor T cell therapy: Insights into mechanisms and novel therapies. Frontiers in Immunology. 2020; doi:10.3389/fimmu.2020.01973.

Expanding engineered cellular therapy

Using engineered constructs and preclinical models for cancer and colitis, the lab is investigating how to apply CAR-T cell therapy to treat other cancers, such as thyroid cancer, GI cancers and brain cancer, as well as to treat autoimmune diseases, such as graft-versus-host disease.

Team

• Mehrdad Hefazi Torghabeh, M.D.
• Truc N. Huynh, M.S.
• Lionel A. Kankeu Fonkoua, M.D.
• Ekene J. Ogbodo, Ph.D.
• Michael W. Ruff, M.D.
• Liz L. Siegler, Ph.D., M.S.
• Olivia L. Sirpilla

Collaborators

• Mitesh J. Borad, M.D.
• John A. Copland III, Ph.D.
• Jann N. Sarkaria, M.D.

Relevant published highlights

• Ruff M, Sakemura R, Cox M, Torghabeh MH, Roman Moreno P, Schick K, Sarkaria J, Kenderian S. Development of EphA3 directed chimeric antigen receptor T cell therapy for the treatment of glioblastoma multiforme. Neuro-Oncology. 2019; doi:10.1093/neuonc/noz175.364.

Producing CAR-T cells more efficiently

The process of generating CAR-T cell therapy is complex and involves cell collection, expansion and viral transduction, followed by cell administration after low-dose chemotherapy. This process is expensive, time-consuming (3-4 weeks) and labor-intensive.

Two strategies are being researched in the lab to overcome these limitations: generating CAR-T cells in vivo (without the need for ex vivo expansion) and generating nonviral CAR-T cells.

Team

• Leo Sakemura, M.D., Ph.D.
• Liz L. Siegler, Ph.D., M.S.

Collaborators

• Stephen J. Russell, M.D., Ph.D.

Relevant published highlights

• Siegler EL, Simone BW, Sakemura R, Tapper EE, Horvei P, Cox MJ, Hefazi M, Manriquez Roman C, Can I, Schick KJ, Ruff MW, Ekker SC, Kenderian SS. Efficient gene editing of CART cells with CRISPR-Cas12a for enhanced antitumor efficacy. Blood. 2020; doi:10.1182/BLOOD-2020-141115.

Clinical trials directly based on the laboratory's work (ongoing)

• Study of Lenzilumab and Axicabtagene Ciloleucel in Subjects with Relapsed or Refractory Large B-cell Lymphoma, sponsored by Kite Inc., a Gilead company.
• A Study to Evaluate Effectiveness and Safety of Lenzilumab in Hospitalized Patients with COVID-19 Pneumonia, NCT04351152, sponsored by Humanigen Inc.
• A phase 1 clinical trial of in-house manufactured CART19 in patients with B cell malignancies, sponsored by Mayo Clinic.

Research highlights

• Cox M, Lucien F, Sakemura R, Boysen JC, Kim Y, Horvei P, Manriquez Roman C, Hansen M, Tapper EE, Siegler EL, Forsman C, Crotts SB, Schick KJ, Hefazi M, Ruff MW, Can I, Adada M, Bezerra E, Kankeu Fonkoua L, Nevala WK, Braggio E, Ding W, Parikh SA, Kay NE, Kenderian SS. Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia. Molecular Therapy. 2020; doi:10.1016/j.ymthe.2020.12.033.
• Ruff M, Sakemura R, Cox M, Torghabeh MH, Roman Moreno P, Schick K, Sarkaria J, Kenderian S. Development of EphA3 directed chimeric antigen receptor T cell therapy for the treatment of glioblastoma multiforme. Neuro-Oncology. 2019; doi:10.1093/neuonc/noz175.364.
• Sterner RM, Cox MJ, Sakemura R, Kenderian SS. Using CRISPR/Cas9 to knock out GM-CSF in CAR-T cells. Journal of Visualized Experiments. 2019; doi:10.3791/59629.
• Khadka RH, Sakemura R, Kenderian SS, Johnson AJ. Management of cytokine release syndrome: An update on emerging antigen-specific T cell engaging immunotherapies. Future Medicine. 2019; doi: 10.2217/imt-2019-0074.
• Sterner R, Sakemura R, Cox M, Yang N, Khadka R, Forsman C, Hansen M, Jin F, Ayasoufi K, Hefazi M, Schick K, Walters D, Ahmed O, Chappell D, Sahmoud T, Durrant C, Nevala W, Patnaik M, Pease L, Hedin K, Kay N, Johnson A, Kenderian S. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019; doi:10.1182/blood-2018-10-881722.