Adoptive cell therapy and cytokine release syndrome

Standard of care systemic therapy for recurrent thymic epithelial tumors (TETs) is generally limited to single agent cytotoxic chemotherapy or the use of targeted biologic agents until disease progression or development of intolerable adverse events (1). Immune checkpoint inhibition with anti-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy is now routinely used in various settings across most tumor types, but its application for patients with TETs is limited to treatment of recurrent thymic carcinoma due to a high risk for development of immune-mediated toxicity (2-4). While “immunotherapy” is often used interchangeably with immune checkpoint inhibitors (ICIs), this umbrella terminology extends well beyond ICIs and encompasses a broad array of anti-cancer therapeutic approaches with a common strategy that aims to harness various aspects of the immune system to enhance its ability to recognize and eradicate malignant cells (5,6). Immunotherapeutic strategies to date include ICIs, cancer vaccines, cytokine-based therapies, oncolytic virotherapies, and adoptive cell therapies (ACT) (5-9). The use of ACTs for treatment of advanced solid tumors is an area of active investigation, and these interventions could potentially have a role for treatment of TETs in the future. In our presentation, we briefly review ACTs and describe cytokine release syndrome (CRS), which is one of the most common post-infusion complications of ACT.

ACT

The ultimate aim of ACT is to generate a robust immune-mediated antitumor response via manipulated immune cells. ACTs, specifically chimeric antigen receptor (CAR)-T cells, were first investigated in patients with hematologic malignancies and have demonstrated unprecedented success leading to Food and Drug Administration (FDA) approvals for six CAR-T cell therapy products to date for patients with relapsed/refractory B-cell malignancies including B-cell acute lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma (10,11). While the development of ACTs for solid tumors is still largely in preclinical stages or in early phase trials, there are more than 150 actively enrolling ACT clinical trials for various solid tumors (12). ACT involves identification, isolation, and autologous collection of the selected immune cell subset, most commonly T cells. These cells then undergo ex vivo manipulation to improve antitumor activity, either through activation and expansion of existing autologous immune cells, such as seen with tumor-infiltrating lymphocytes, or genetic modification of cells to express receptors that recognize tumor-associated antigens and can induce cell death, as seen with CAR-T cells (7-9). Following manipulation, cells undergo in vitro expansion to achieve the desired cell dose and then are given via simple infusion. Prior to cell infusion, patients are treated with a conditioning regimen, commonly with cyclophosphamide and fludarabine, causing transient host lymphodepletion to maximize further cell expansion and activity (7-10,13). As with other investigational agents in development, ACTs must demonstrate an acceptable toxicity profile while maintaining clinical activity. When evaluating safety for a given cellular product, it is critical to understand the sequential steps by which this treatment modality is delivered as each aspect of the platform can contribute to both toxicity and efficacy. While the cellular product infusion is straightforward and generally tolerated well, the post-infusion inflammatory responses can result in significant toxicities, most commonly in the form of CRS.

CRS

CRS is characterized by a proinflammatory milieu of immune cell activation, primarily T and myeloid cells, and secretion of immune proteins, such as soluble factors and interleukins (7,8,14-17). The American Society for Transplantation and Cellular Therapy (ASTCT) 2019 Consensus Guidelines defined CRS as a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells and published a standardized grading system for broad applicability across institutions and cellular immunotherapies (17). Risk factors for CRS include a high tumor burden, rapidly progressing disease, specific CAR construct proteins, lack of lymphodepletion, high doses of cellular product, and in vivo cell product expansion (14,15,18).

Clinically, CRS presents as fever and can be accompanied by non-specific constitutional symptoms (grade 1) progressing in severity to hypoxia and/or hypotension (grade 2), capillary leak, end organ dysfunction, and/or cardiopulmonary decompensation; CRS requiring one vasopressor and/or high flow nasal cannula is considered grade 3, while grade 4 CRS is when multiple vasopressors and/or positive pressure oxygen support are required (17). The onset and duration of CRS varies based on patient and disease characteristics in addition to the cellular product/platform and use of any prophylactic, pre-emptive, or therapeutic interventions for CRS and is not limited to a specific timeframe. Per ASTCT Consensus Guidelines, there should be a reasonable temporal relationship to the cellular therapy infusion. Generally, the median onset of any grade CRS is within 1–3 days of infusion, rarely presenting beyond 14 days, with a duration of about 7 days (14,15,17).

CRS left untreated can be rapidly fatal and requires prompt assessment and early intervention to decrease the overwhelming, systemic inflammatory response with immunosuppressive strategies including tocilizumab (IL-6 receptor binding antibody), corticosteroids, and/or inhibition of inflammatory cytokine signaling (7,10,15). Tocilizumab with supportive care is the frontline treatment for CAR-induced CRS and is FDA approved for this indication (15,16). In tocilizumab-refractory cases, corticosteroids are routinely used as second line therapy while adjunct immunosuppressive interventions such as anakinra (IL-1 receptor antibody), siltuximab (IL-6 binding antibody), emapalumab (IFN-γ binding antibody), anti-thymocyte globulin, alemtuzumab, and cyclophosphamide have been used off label in cases of severe or life-threatening CRS (15). Of note, it is imperative to rule out concomitant immune effector cell-associated neurotoxicity syndrome (ICANS) as tocilizumab does not cross the blood-brain barrier, therefore rendering it ineffective, and treatment with corticosteroids as front-line therapy is indicated (7,14,15). Ongoing clinical trials evaluating the role of CRS prophylaxis with tocilizumab or alternative immunosuppressive agents are underway and may change the current paradigm of CRS management.

In conclusion, ACTs hold immunotherapeutic potential when a tumor-specific antigen or target can be identified. If successful, the ACT platform can potentially be utilized to develop newer treatments for TETs. However, ACTs can invoke robust inflammatory responses, resulting in toxicities such as CRS and ICANS, which must be treated promptly and aggressively with anti-cytokine-directed treatments and corticosteroids. Translating ACTs to TETs requires careful consideration of treatment components, including the potential for development of excessive, unchecked inflammation, which is especially relevant due to defective immune tolerance associated with TETs.

Acknowledgments

Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (No. ZID BC 011543).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-8/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-8/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Copyright Information: The authors of this manuscript are U.S. Government employees. Since this manuscript has been prepared within the scope of their employment, it should be considered to be in the public domain in the USA and not require a transfer or license of rights.

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