Abstract
Chimeric antigen receptor–modified T (CART)-cell–based targeting of solid tumors remains a considerable and worthwhile challenge in the field of immunotherapy. The role of chemotherapy to target stroma and enhance chimeric antigen receptor (CAR) cell antitumor function, expansion, and persistence is still unresolved. Clin Cancer Res; 24(6); 1246–7. ©2018 AACR.
See related article by Guo et al., p. 1277
In this issue of Clinical Cancer Research, Guo and colleagues (1) report on a clinical study designed to evaluate stromal targeting to enhance EGFR-specific chimeric antigen receptor–modified T (CART)-cell (CART-EGFR)–based therapy of biliary cancers. The authors demonstrate clinical and pharmacodynamic measures of activity and provide evidence for a potential measure of product potency. The potential to apply synthetic biology and effectively target cancer has been exemplified by the remarkable success of CART therapy in the setting of hematologic malignancies (2). To date, effective targeting of solid tumors using engineered T cells has not achieved the success observed in leukemias for reasons that are likely multiple and include T-cell intrinsic as well as extrinsic factors related to the complexity of the tumor milieu, as well as issues related to the paucity of appropriate targets and engineering constraints (3). Guo and colleagues report on a clinical trial designed to evaluate CART-based targeting of EGFR-positive advanced biliary cancer. The current report is a follow-up to an original study by the same group that provided early evidence for activity for this approach (4). In the current study, investigators expand on their earlier observations and specifically seek to evaluate the impact of stromal targeting on the efficacy of CART immunotherapy in a cohort of 19 patients with advanced biliary tract cancer (14 cholangiocarcinoma and five gallbladder). In addition, investigators also evaluate pharmacodynamic and product attributes that might correlate with CART activity.
In line with essentially all other to-date reports for CART-based targeting of solid tumors, the data presented in this report fall far short from those generated in the context of hematologic malignancies. Nonetheless, this report adds potentially meaningful and relevant insights to the collective dataset of information that will lead to solving the puzzle of engineered T-cell therapy for solid tumors.
Investigators employed a CART design and engineering strategy modeled after the University of Pennsylvania experience, with a chimeric antigen receptor (CAR) construct design that included signaling domains for CD137 and TCRζ, and delivered to T cells using lentivirus transduction, and engineered T cells expanded ex vivo by artificial stimulation using CD3/C28 beads.
Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 and at least 50% EGFR+ tumors were infused in an escalating dosing schema over a period of 3 days with expanded engineered T cells. On the basis of data from their original report, investigators administered a conditioning regimen consisting of nab-paclitaxel and cyclophosphamide just prior to T-cell infusion, hypothesizing that this regimen would target and deplete tumor stroma by binding to SPARC proteins and dysregulating the stromal milieu. An additional cohort of three patients, defined as “special patients,” received the CART therapy under compassionate use without the conditioning regimen.
In terms of evaluating the full potential of this therapy and regimen to impact EGFR+ biliary cancers, this study is compromised in a number of ways. The mean transduction efficiency of the final engineered product was less than 10%, and engineered cells did not demonstrate the robust in vivo expansion and persistence that is a hallmark of successful CART therapy. In addition, the issue of immunogenicity of the engineered cells is not addressed, and the derivation of the EGFR targeting sequences (murine, humanized, other) was not made clear. Importantly, the lack of on-treatment tumor tissue to assess the impact of the regimen and treatment on stroma prevents any meaningful ability to assess the key hypothesis tested in these studies.
In terms of efficacy, this report provides additional encouraging but ultimately inconclusive data to add to the collective CART experience in solid tumors: Of 17 evaluable patients, one achieved a complete response and 10 achieved stable disease. The median PFS of 4 months is most likely noninformative given the patient performance status and small sample size.
From a pharmacodynamic perspective, the study provides further evidence for the ability of engineered cells to function in patents with solid tumors. Treatment-expected toxicities including conditioning-related transient lymphopenia, thrombocytopenia, and anemia were observed; as well as CART function–related acute fever and chills; and EGFR-targeting–related acute pulmonary edema, which was reversible by tocilizumab (anti-IL6 receptor) intervention. Intriguingly, the authors also identified a central T memory (TCM) phenotype that was enriched in engineered cell products from patients who achieved a clinical response [complete response (CR) or stable disease (SD)] relative to the nonresponding patients. This observation is compromised by two issues beyond the limited dataset of patients: First, the reported TCM phenotype was a property of the entire expanded population and not the engineered subset whose phenotype was not defined, and additionally by the reality that it is particularly difficult to assign a differentiation status to cells immediately following ex vivo expansion based on surface markers; nonetheless, this observation provides an actionable potential biomarker for engineered cell product potency that can be explored in future studies.
Of additional note was the outcome for the three compassionate-use special patients who did not receive conditioning treatment (SP cohort). Despite the absence of conditioning, each of these patients showed a clinical response to the therapy [one CR, one partial response (PR), and one SD]. Although the mean TCM percentage for the SP cohort was higher than the mean for the progression of disease (PD) group, and each of these patients had additional confounding features that might suggest compromised stroma (prior radiotherapy, pleural effusion disease, and multiple small metastases), these results further complicate the ability to assess the impact of targeting stroma on treatment efficacy.
In summary, the report by Guo and colleagues (1) provides further rationale to explore the targeting of solid tumors in general and biliary cancers in particular using CAR-engineered T-cell–based strategies in conjunction with targeting of tumor stroma (Fig. 1). Perhaps not surprisingly, this study generated more questions than answers; however, signals of clinical activity and pharmacodynamic measures of CART activity were observed, and a potential measure of product potency was identified in this study, providing encouraging signals for future development of a more potent version of this approach.
Disclosure of Potential Conflicts of Interest
M. Kalos has intellectual property interest in the use and commercialization of CART therapy (University of Pennsylvania, intellectual property assigned to Novartis).