Potentiation of Efficacy of Chimeric Antigen Receptor (CAR) T-cell Therapy in Hematological Malignancies using FDA-Approved Small Molecule Sensitizing Agents

Abstract

Anthony Morales, Ali R Jazirehi

Chimeric antigen receptor CD19 CAR T-cell therapy has received FDA-approval for treatment of B cell malignancies. CD19 is an ideal target for B cell malignancies due to its limited expression by B lineage cells. Non-Hodgkin’s Lymphoma of B-cell origin (NHL B-cell) accounts for about 4% of all cancers in the United States. Traditionally, combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) was considered as standard treatment option for NHL patients. However, a subset of individuals was inherently resistant to CHOP or developed resistance upon continued exposure to chemotherapy. The development of drug-resistance, plus the undesired toxic side effects of this regimen, led to the inclusion of anti-CD20 mAb, Rituximab, to chemotherapy protocols of NHL patients (R-CHOP). Superior improvement was observed in patients undergoing R-CHOP compared to CHOP. More recently, chimeric antigen receptor (CAR) T-Cells redirected against CD19 (CD19 CAR T-cell) has proven to be an effective immunotherapy against various cancers including NHL. Despite initial success, and like other approaches, NHL patients become unresponsive to CD19 CAR T-Cells due to selective outgrowth of NHLs with deregulated expression of apoptotic proteins. Histone deacetylase inhibitors (HDACis) and celecoxib have gene regulatory effects and skew the tumor intracellular environment into a proapoptotic milieu. Thus, resistant NHL cells will become sensitized to apoptotic death signals delivered by CD19 CAR T-Cells. We propose the inclusion of FDA-approved small molecules as sensitizing agents to reduce the apoptosis threshold of resistant NHL and boost CD19 CAR T-cell efficacy.

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