Engineered (C)himeric (A)ntigen (R)eceptor (CAR) T cells show unprecedented level of protection against fluid tumors such as myelomas and lymphomas in clinical trials. The vast majority of these trials are based on CAR T cells with α-CD19 specificity. CD19 is a B cell specific marker and it is involved in B cell receptor signaling.
It is not immediately obvious why α-CD19 CAR T cells show such superior activity compared to CAR T cells with other specificity. One study suggested that α-CD19 CAR construct itself is uniquely effective. Another possibility is that since α-CD19 CAR T cells targets are a fluid populations such as B cells and B cell-derived tumors, they are highly sensitive for T cell mediated cytotoxicity.
In this regard, it is of interest to review a new paper published in Cancer Cell (part of Cell publication). Here, the authors have assessed efficacy of next-gen α-CD19 CAR constructs that incorporated several co-stimulatory molecules.
Initially, the authors compared 1st and 2nd generation α-CD19 CAR T cells designated here as 19z (α-CD19 CAR + CD3zeta), 1928z (α-CD19 CAR + CD28 + CD3zeta) and 19BBz (α-CD19 CAR + 4-1BB + CD3zeta). Here, 1928z CAR construct showed superior activity against myeloma, as measured in overall survival assay.
However, when the authors have analyzed CAR T cells expansion and tumor cell reduction in bone marrow at day 21, no difference was found between 1928z and 19BBz. Thus mice survival data and bone marrow data did not match. This complicates interpretation of this study.
Next, the authors showed that next-gen α-CD19 CAR construct incorporating two set of co-stimulatory molecules showed enhanced anti-tumor activity compared to 2nd generation α-CD19 CAR T cells (but not all combinations were effective and some were even detrimental).
Yet again, when the authors have analyzed CAR T cells expansion and tumor cell reduction in bone marrow at day 21, minimal difference was found between "active" CAR constructs. Thus, mice survival data and bone marrow data did not match. This complicates interpretation of this study.
In summary, we can conclude that incorporation of several co-stimulatory molecules in next-gen CAR constructs may enhance their anti-tumor activity, but we need better models to study relationship between CAR T cells anti-tumor activity and their cellular response.
David Usharauli
It is not immediately obvious why α-CD19 CAR T cells show such superior activity compared to CAR T cells with other specificity. One study suggested that α-CD19 CAR construct itself is uniquely effective. Another possibility is that since α-CD19 CAR T cells targets are a fluid populations such as B cells and B cell-derived tumors, they are highly sensitive for T cell mediated cytotoxicity.
In this regard, it is of interest to review a new paper published in Cancer Cell (part of Cell publication). Here, the authors have assessed efficacy of next-gen α-CD19 CAR constructs that incorporated several co-stimulatory molecules.
Initially, the authors compared 1st and 2nd generation α-CD19 CAR T cells designated here as 19z (α-CD19 CAR + CD3zeta), 1928z (α-CD19 CAR + CD28 + CD3zeta) and 19BBz (α-CD19 CAR + 4-1BB + CD3zeta). Here, 1928z CAR construct showed superior activity against myeloma, as measured in overall survival assay.
However, when the authors have analyzed CAR T cells expansion and tumor cell reduction in bone marrow at day 21, no difference was found between 1928z and 19BBz. Thus mice survival data and bone marrow data did not match. This complicates interpretation of this study.
Next, the authors showed that next-gen α-CD19 CAR construct incorporating two set of co-stimulatory molecules showed enhanced anti-tumor activity compared to 2nd generation α-CD19 CAR T cells (but not all combinations were effective and some were even detrimental).
Yet again, when the authors have analyzed CAR T cells expansion and tumor cell reduction in bone marrow at day 21, minimal difference was found between "active" CAR constructs. Thus, mice survival data and bone marrow data did not match. This complicates interpretation of this study.
In summary, we can conclude that incorporation of several co-stimulatory molecules in next-gen CAR constructs may enhance their anti-tumor activity, but we need better models to study relationship between CAR T cells anti-tumor activity and their cellular response.
David Usharauli
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