CD19 antigen negative relapse
Patients treated CD19 CAR T cells may experience CD19-negative relapse. Three mechanistic hypotheses have been suggested in: antigen loss or modulation, inherent tumor heterogeneity with pre-existing CD19 negative subclones, and lineage switching. In antigen loss and modulation, pathways leading to the loss of CD19 includes alternate splicing (exon 2 skipping) 57, interruption in the transport of CD19 to the cell surface due to mutations 58, or mutations in the CD19 chaperone protein CD81 59. Secondly, it is also possible that pre-existing CD19 negative subclones are present at diagnosis, which allows for emergence of CD19 negative leukemic blasts60. Specifically, patients with BCR-ABL1 positive B-ALL have been shown to harbor CD19 negative malignant precursor cells61; although, further studies are needed to determine whether certain cytogenetics are associated with higher occurrences of inherent tumor heterogeneity with more CD19 negative subclones. Thirdly, lineage switch is another mechanism for CD19 loss. Although it is traditionally associated with infant KMT2A-rearranged leukemic subtypes62, CAR T cell clinical trials have also reported lineage switch from lymphoid to myeloid leukemic subtypes regardless of KMT2A rearrangement 56,63. This phenomenon has also been seen with other CD19 directed therapy, such as blinatumomab64, which highlights the concept that leukemic blasts with certain cytogenetics may show exceptional plasticity in response to their microenvironment; therefore, careful monitoring for escape variants cannot be overemphasized. Though the use of blinatumomab is effective in disease control in with relapsed/refractory B-ALL65, especially at MRD levels of disease. its prior use may contribute to the increased risk of immune evasion after CAR therapy due to selection pressure for CD19-negative malignant cells. Due to these concerns, treatment with prior anti-CD19 therapy such as blinatumomab was an exclusion criterion in the ELIANA trial21. Subsequent analysis of 166 patients who received tisagenlecleucel confirmed this suspicion by demonstrating that prior therapy with blinatumomab was associated with a significantly higher rate of failure to achieve MRD negative remission or subsequent loss of remission with antigen escape that was not associated with the presence of dim CD19 or rare CD19 negative events by flow cytometry prior to tisagenlecleucel infusion 66. However, we do not regard prior CD19-directed therapy as. A contraindication for tisagenlecleucel infusion. Lastly, a unique case was recently reported showed introduction of the CAR gene into a single leukemic B cell during T cell manufacturing. An ALL patient treated on our studies relapsed with CD19 negative leukemia 9 months after he received tisagenlecleucel. It was unclear whether the CAR gene resulted in the relapse, but one hypothesis was that the CD19 molecule was masked but the CRA protein. In this single case, the relapse resulted from a single ALL cell as shown by site integration analysis 67.
For patients with antigen negative relapse, targeting of other antigens such as CD22 using inotuzumab ozogamicin or a CD22-directed CAR T product are viable options, but no data on the curative potential of either exist and further prospective studies are needed68,69. Therefore, at this time, allogeneic HSCT remains as the only option for definitive therapy after achievement of second remission in this population.