CAR-T Cell Therapy for Lymphoma: How Does Radiation Therapy Fit In?

Introduction

Personalized immunotherapies have altered the landscape of oncologic prognostics and care for hematologic malignancies. Chimeric antigen receptor (CAR)-T cell therapy is one immunotherapy that has revolutionized the way we conceptually and mechanistically approach malignant cell eradication. Because CAR-T cell therapy is still largely in its infancy, our optimization of treatment-related variables is central to this new era of targeted cancer therapy.

Here we present a multidisciplinary paradigm for how to approach patients with relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) receiving CAR-T cell therapy using radiation therapy (RT). We discuss the current state of r/rNHL therapies, summarize the existing literature on RT and CAR-T cell therapy, and propose a strategy to bridge therapy involving RT.

Background

Diffuse large B cell lymphomas (DLBCL) comprise the greatest proportion of new NHL diagnoses.¹ For patients with stage I or II disease, standard of care is 3 to 6 cycles of systemic chemoimmunotherapy using rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone with or without involved-site RT. Stage III/IV disease is typically managed with chemotherapy alone. Progression-free survival (PFS) is improved when RT is added to chemotherapy if masses are larger than 7.5 cm, have an incomplete metabolic response, or have skeletal involvement.^2–8

Despite aggressive treatment, many patients still recur or fail to respond to therapy at all, with 5-year PFS estimated at 65% to 85% in early-stage disease^2,9 and 45% to 75% in advanced-stage disease.^2,10 Salvage chemotherapy with autologous hematopoietic stem cell transplant (HCT) results in superior response rates, event-free survival, and overall survival (albeit with greater treatment-related toxicity) over chemotherapy alone.¹¹ However, only 50% of patients with r/rNHL typically meet eligibility criteria for HCT secondary to other comorbidities, and of those who are transplant eligible, only some respond to salvage chemotherapy before transplant.

Rare patients with limited-stage disease can be salvaged with RT alone, but success rates are low. Allogeneic HCT has been (and in some centers still is) used, but 3- to 5-year PFS in NHL is reported at 30% to 40%.^12–15 Although the options for r/rNHL have greatly expanded with the development of novel agents, even targeted agents generally only work for so long. However, novel immunotherapies such as CAR-T cell therapy may be changing expectations by offering the potential for cure in patients previously considered incurable.

CAR-T Cell Therapy in Relapsed and/or Refractory NHL

CAR-T cell therapy is a customized treatment involving transfection of a patient’s own T lymphocytes ex vivo with a gene encoding an “activating” chimeric transmembrane protein, followed by expansion of the cells in a specialized production facility and infusion back into the patient approximately 3 weeks later (Fig 1). The chimeric protein itself is a combination of the antigen recognition motif (anti-CD19 in Food and Drug Administration [FDA]-approved products) and the T cell receptor zeta chain, which enables modified T cells to recognize and kill cancer cells. “Second-generation” CAR-T cells also contain a costimulatory domain (CD28 or 41BB in the approved products) that enhances their activity. Based on CAR-T cell studies in leukemia, patients also receive lymphodepleting chemotherapy, commonly fludarabine and cyclophosphamide, several days before infusion with the intention of using host lymphopenia to create space for and indirectly induce transferred T cell expansion.¹⁶ However, these therapies are not effective against r/rNHL, and thus additional antitumor “bridging” therapy has been variably employed for disease control during the manufacturing period before lymphodepletion.

Figure 1.

Chimeric antigen receptor T cell preparation process. The process begins with steady-state leukapheresis for T cell collection and T cell subset selection. This is followed by gene modification of the T cells, achieved through lentiviral vector transfer, retroviral vectors, or electroporation. Modified cells then undergo short-term culture for expansion and activation with anti-CD3 antibodies, agonistic anti-CD38 antibodies, and sometimes exposure to exogenous cytokines (IL-2, IL-7, IL-12, IL-15). Before reinfusion of T cells back into the patient, lymphodepleting therapy can be administered with fludarabine-cyclophosphamide; for tisagenlecleucel specifically, bendamustine can be substituted or chemotherapy can be omitted. The red star indicates the optimal time point at which RT may be incorporated.

Axicabtagene ciloleucel (axi-cel) is a “second-generation” CAR-T cell product with CD28 as the costimulatory domain. In October 2017, the FDA approved axi-cel at a target dose of 2 × 10⁶ anti-CD19 CAR-T cells/kg for r/rDLBCL, transformed follicular lymphoma, primary mediastinal large B-cell lymphoma, or high-grade B cell lymphoma based on ZUMA-1, an open-label, multicenter trial of 108 patients demonstrating 1-year objective and complete response rates of 82% and 58%, respectively, and PFS of 41% at 15 months. In ZUMA-1, no bridging therapy was allowed, and lymphodepletion was accomplished with cyclophosphamide (500 mg/m²/d) and fludarabine (30 mg/m²/d). Tisagenlecleucel (tisa-cel), a CD19 CAR-T cell therapy using the 41BB costimulatory domain, was tested in the JULIET trial, a single-arm, open-label, multicenter phase 2 trial in 93 patients with r/rDLBCL. This showed an overall response rate of 50% and a 1-year relapse-free survival rate of 65% and led to the FDA approval of tisa-cel, previously approved for pediatric acute lymphoblastic leukemia. In the JULIET trial, 90% of patients received bridging therapy, most commonly rituximab (54%) or gemcitabine (40%), and 93% received lymphodepleting chemotherapy (required if white cell count was >1000 cells/mm³) with either fludarabine (25 mg/m²/d) and cyclophosphamide (250 mg/ m²/d) for 3 days or bendamustine (90 mg/m²/d) for 2 days.¹⁷

A concerning risk of CAR-T cell therapy is potentially fatal or debilitating toxicity. The 2 primary serious complications are cytokine release syndrome (CRS) and neurotoxicity (CAR-T cell–related encephalopathy syndrome). Although CRS can be reversed with the prompt use of anti-interleukin 6-receptor therapy (tociluzumab) or steroids, patients with CRS are frequently admitted to intensive care units. Neurotoxicity is less common but more difficult to manage. Other generally treatable toxicities of lymphodepletion and CAR-T cell infusion include hypersensitivity reactions, prolonged cytopenias, serious infections, and prolonged hypogammaglobulinemia.

A frequent critique of CAR-T therapy is the overwhelming cost, which includes the product itself and the ensuing resources engaged when toxicities occur. Ultimately, clinical benefit and potential long-term disease control have to be weighed against toxicity risk, but safer delivery is an important goal.

Axi-cel and tisa-cel have been in use now for over 1.5 years. However, with these new therapies come questions that would benefit from evidence generation. Which real-world patients are reasonable candidates? What can be done to minimize patient (and financial) toxicity? Who needs bridging therapy, what type, and when? Currently patients with r/rDLBCL who are CD19-positive and have progressed after ≥2 lines of therapy are candidates for CAR-T therapy. Typical reasons for exclusion are active central nervous system disease, poor performance status, or rapid progression, the latter being most challenging. Some patients can be stabilized with preleukapheresis therapy; however, adequate lymphocyte counts (>300/mm³)¹⁸ are required for successful apheresis. Bridging therapy should ideally elicit at least a partial response, but this can be challenging in heavily pretreated patients. Cytoxics, anti-CD20 antibodies, ibrutinib, venetoclax, and revlimid are potential options, but responses are unreliable in the r/r population. With less cross-resistance, RT can fill a unique bridging niche.

Tandem Sequencing of RT and CAR-T: A Practical Approach to Bridging Therapy

Chemotherapy-resistant lymphomas are frequently sensitive to RT.¹⁹ Because RT is lymphodepleting, it should be delivered after leukapheresis during the manufacturing window with or without systemic therapy to ensure adequate absolute lymphocyte counts for collection. CAR-T cell candidates who may benefit from RT include patients with (1) symptomatic regions requiring palliation, (2) large volumes of lymphoma in contiguous regions, (3) limited distribution of relapse that can be encompassed in RT fields, or (4) progressive disease requiring treatment before insurance gives authorization, leukapheresis can be scheduled, or CAR-T cell manufacture and quality assurance are complete. One tantalizing rationale for RT is that it may reduce CART–specific toxicities by reducing the lymphoma burden (linked to CRS rates in leukemia^20,21) while also treating chemorefractory, symptomatic, or progressing disease, warranting analysis in future prospective trials. Second, RT may enhance CAR-T cell activity, as was suggested in pancreatic and glioblastoma cell lines.^22,23 Evidence for a synergistic, abscopal-like response to CAR-T therapy and localized RT was suggested in a recently published case of multiply relapsed refractory myeloma.²⁴ Lastly, when all known disease can be targeted within reasonable fields, RT alone as salvage has a small chance of cure, even if the CAR-T cells are unsuccessful.

In the first report of RT as a bridge to CAR-T therapy, Arscott et al found no grade 3 or higher CRS after RT-based cytoreduction/lymphodepletion in 5 tisa-cel patients. Additionally, 1-year PFS among patients who received induction RT (<30 days before CAR-T infusion) was favorable (78%) compared with those who did not (44%).²⁵ Sim et al reported on 12 patients treated with RT bridging therapy and axi-cel with or without concurrent chemotherapy.²⁶ In their series, 8 patients had disease ≥10 cm; half were treated with 10 × 3 Gy or 5 × 4 Gy, and 80% responded to RT. They did observe lymphocyte count decreases after RT, but treatment was otherwise deemed safe. Imber et al reported on 13 patients treated with bridging RT and CAR-T products in DLBCL, most commonly after apheresis with 5 × 4 Gy.²⁷ All of these studies are too small to suggest an impact of bridging RT on efficacy or toxicity. However, in practice, patients undergoing CAR-T cell therapy are being referred for RT, most commonly between apheresis and lymphodepletion. Dose and fractionation regimens have varied, but hypo-fractionated palliative regimens seem reasonable, especially when all disease cannot be targeted. When the referral is made in advance, a more protracted regimen to deliver higher biologically effective doses can be considered. Regarding RT-related toxicity pre-CAR-T, common sense dictates blood count monitoring and avoidance of RT-related toxicity that would necessitate steroids (eg, radiation pneumonitis), because steroids are lethal to CAR-T cells. Limiting RT dose to bone marrow is preferable, especially for patients who are scheduled for marrow-toxic lymphodepletion, and prophylactic oral antiviral therapy can be used to prevent zoster outbreaks.

Conclusions

CAR-T therapy for r/rNHL has ushered in an exciting time for treatment of patients with refractory disease. RT represents a potentially unique component to CAR-T therapy through its ability to palliate, focally cytoreduce, lymphodeplete, and immunologically enhance relevant tissue, ultimately maximizing the number of patients who reach the infusion stage and minimizing treatment-related toxicity. Preliminary data on the use of RT as a bridging therapy warrant investigation in future CAR-T trials.