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Case Reports
LAG3 expression was low prior to pembrolizumab but rose after treatment (not shown). There were insufficient cells to analyze T-cell activation markers.
Mechanisms of resistance to bispecific CAR T are unclear to date. In both patients, target antigen loss was not identified, and there were high levels of CAR T persist- ence at relapse. While patient 1 had increased tumor bulk and an elevated pre-infusion lactate dehydrogenase (LDH) (501 mg/dL) which correlates with worse outcomes with CAR T therapy,7 patient 2 had no predictive markers of poor response. Off label pembrolizumab was administered to counter potential upregulation of tumoral checkpoint inhibitors and minimize T-cell exhaustion in the CAR T cells to augment CAR T efficacy. For patient 1, despite decreased PD-1 expression and an increase in cytotoxic T cells, there was minimal response with no meaningful durability. For patient 2, after pembrolizumab there was an initial decrease in PD-1 expression and increase in cyto- toxic T cells, but this was quickly followed by increases in all markers of T-cell exhaustion and decrease in the cyto- toxic T-cell ratio. For unclear reasons, CAR T levels in patient 2 continued to rise after PD-1 blockade despite the lack of efficacy. During this time the patient received R- GemOx and pola-BR and ultimately achieved a CR with salvage therapy and remains in an ongoing remission post- allogeneic HCT. Our experience appears similar to reports of PD-1 inhibitors after failure of anti-CD19 CAR T cells. While an initial report suggested pembrolizumab after pro- gression with anti-CD19 CAR T enhanced CAR T activity in primary mediastinal B-cell lymphoma (PMBCL), this class of agents has meaningful single agent activity in PMBCL so it is unclear if the combinatorial regimen had added benefit.4,8 Another report described a patient with DLBCL with PET-CT confirmed progression on day 7 after axicabtagene ciloleucel.5 He was given nivolumab on days 11, 23 and 35 and day 35 CT showed PR, but day 64 scans demonstrated PD. In a prospective single-center study, only three of 11 patients who received pembrolizumab after failure of anti-CD19 CAR T had responses (one CR and two PR), which is only slightly higher than the single agent activity of PD-1 inhibitors in DLBCL.9 Although PD- L1 expression was low in the post-CAR T relapse biopsies of these two patients at 1-10%, only approximately 30% of cases of DLBCL have ≥5% PD-L1 expression.10 Whereas PD-L1 expression seems to correlate with response rate in Hodgkin lymphoma and chronic lymphocytic leukemia, the predictive value of PD-L1 expression on response in DLBCL is less clear.11 Despite this, there remains high interest in combining PD-1 inhibitors with CAR T therapy, including an ongoing trial of pembrolizumab given with or immediately after dual targeted anti-CD19, anti-CD22 CAR T therapy.12 While this report and others have demonstrated low response rates with anti-PD1 at relapse after CAR T, the benefit of PD-1 inhibitors given concur- rently with CAR T therapy remains unclear.7 Further research is needed to determine the etiology of treatment failures in these described cases. We have recently demon- strated that the baseline T-cell transcriptome along with cytokine signature and polyfunctionality of the CAR T product may predict clinical response in patients treated with LV20.19 CAR T cells.13,14 Whether this data can be used to create a more robust CAR T cell that overcomes treatment resistance remains to be seen; however, our experience suggests that after progression with bispecific CAR T cells, PD-1 inhibitors appear unlikely to provide clinically meaningful benefit.
Joanna Zurko,1 Katherine Chaney,1 John M. Astle,2
Bryon D. Johnson,1 Parameswaran Hari1 and Nirav N. Shah1
1BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin and 2Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
Correspondence: NIRAV N. SHAH - nishah@mcw.edu doi:10.3324/haematol.2021.278461
Received: January 31, 2021.
Accepted: April 7, 2021.
Pre-published: April 15, 2021.
Disclosures: BJ recieved research support from Miltenyi Biotec and Cell Vault; PH received research support from Miltenyi Biotec and reports the following consultancy relationships: Incyte Corporation,Takeda, BMS, Amgen, GSK, and Janssen; NNS received honoraria and/or travel support from Incyte, Celgene, Lily, and Miltenyi Biotec, serves on scientific advisory boards for Lily, Kite, Celgene, Legend, Epizyme, and TG thearpeutics; reports equity own- ership in Exelixis and Geron, received institutional research support for clinical trials from Lily and Miltenyi Biotec. All the other authors have no conflicts of interest to disclose.
Contributions: JZ, BJ and NS analyzed data and wrote the paper; KC performed research and analyzed data; JA performed research; PH analyzed data. All authors listed contributed to interpretation of the data and editing of the manuscript.
References
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2. Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569- 1575.
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12. Ardeshna KM, Marzolini MAV, Norman J, et al. Phase 1/2 study of AUTO3 the first bicistronic chimeric antigen receptor (CAR) target- ing CD19 and CD22 followed by an anti-PD1 in patients with relapsed/refractory (r/r) diffuse large B cell lymphoma (DLBCL): results of cohort 1 and 2 of the Alexander Study. Blood. 2019; 134(Suppl 1):S246.
13. Kearl T, Mei A, Brown R, et al. Single-cell RNA sequencing identifies expression patterns associated with clinical responses to dual-target- ed CAR-T cell therapy. Blood. 2020;136(Suppl 1):S33-34.
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