Emerging Cell-Based Treatment in Post-Transplant Lymphoproliferative Disorders

Post-transplant lymphoproliferative disorders (PTLD) represent a heterogeneous group of rare diseases with an incidence of 1% of transplant cases including both allogeneic stem cells (allo-SCT) and solid organ tumor (SOT). The pathogenesis of PTLD is strongly related to immunosuppression conditions and in 2017 the WHO revised the classification of PTLD, distinguishing destructive from non-destructive subtypes. The forms with clinical interest are the destructive, which are the most frequent subtype, associated for more than 90% with EBV infection [1]. The incidence of PTLD post allo-SCT results of 0.6-4%, typically onset within 1 year from transplantation and virtually all cases are Epstein-Barr virus (EBV)-related. PTLD post-SOT occurred with an incidence of 1-33%, generally after 1 year from transplantation and around 60% are EBV associated [2,3]. Generally, three main risk factors are commonly recognized for the development of PTLD: the type of transplant, EBV infection, and the type and duration of immunosuppression (Table 1). In the setting of SOT, the risk of PTLD varies by organ, with the highest risk associated with intestinal transplantation, followed by lung, heart, liver, pancreas and kidney [4]. For allo-SCT, PTLD risk is related to several factors, including HLA mismatch-particularly in haploidentical transplants- the use of anti-thymocyte globulin (ATG), the occurrence of acute and chronic graft-versus-host disease (GvHD), and EBV serological mismatch (EBV-negative recipient with an EBV-positive donor) [5,6]. In the context of PTLD following allo-SCT, a 5-point scoring system has been developed, incorporating three pretransplant risk factors: ATG use, donor type, and aplastic anemia [7]. The clinical presentation of PTLD is highly variable and includes a wide and non-specific spectrum of manifestations, ranging from systemic symptoms such as fatigue, fever and superficial lymphadenopathy to significant organ damage. Diagnosis is based on a combination of non-invasive methods, including EBV DNAemia and imaging techniques (CT, PET, or MRI), while invasive procedures are represented by lymph node biopsy or, in cases of gastrointestinal symptoms, endoscopy with biopsy. Histological examination must include the assessment of viral antigen, immunohistochemistry and flow-cytometry for B and T-cell. The treatment of EBV-PTLD is based on three main strategies which can be summarized in restoring function of T cells, reduction of B-cell burden mass and antiviral treatment (Figure 1) [8]. The therapeutic algorithm of first-line PTLD differs between SOT and HSCT [9]. The backbone of SOT PTLD is represented by the reduction of immunosuppression (RIS) resulting in 45% of overall response rate (ORR), which can be combined with rituximab and/ or lymphoma specific therapy in non-responder’s cases [10]. On the contrary, the first-line therapy of PTLD post-allo-SCT is based on rituximab (375mg/mq for four doses) which induced an ORR of 60-65%, with 2-year median overall-survival (OS) of 50% [11]. It is important to underline that the first-line therapy in both conditions are mostly based on strategies to reduce B-cell mass while, as discussed below, the emerging treatment for the R/R EBV-PTLD cases are based on T-cell restoring drugs.

Figure 1:Strategies for EBV-PTLD treatment [8]. RIS: Reduction of Immunosoppression; DLI: Donor Lymphocyte Infusion; EBV-CTLs: Epstein-Barr Virus Cytotoxic T-cell Lymphocyte; Car-T: Chimeric Antigen Receptor T-cells.

Table 1:Risk factors for PTLD onset [4,5].

Emerging cell-based therapy for R/R PTLD cases

The treatment of R/R EBV-PTLD remains an unmet medical need and is associated with a particularly poor prognosis, with a median OS of 0.7 months [12]. In this context, adoptive immunotherapy with the administration of EBV-specific cytotoxic T lymphocytes (EBV-CTLs) appears to be the most promising approach. From the earliest applications, it became evident that the use of EBV-CTLs in the treatment of PTLD, both post-SOT and post-HSCT, yielded significant results with reduced toxicity and a low risk of GvHD or organ rejection [13]. EBV-CTLs can be derived from the patient himself (autologous), from the original donor, or from a third-party donor. The latter has proven to be the most effective for obtaining EBV-CTLs, due to their off-the-shelf availability, overcoming the prolonged manufacturing time required by other approaches. For this reason, third-party EBV-CTLs have rapidly become the most widely adopted method for the treatment of EBV-PTLD. The prerequisite for the antigen recognition of B cell EBV positive by EBVCTLs is represented by the HLA restriction. So, the patient and donor HLA profile is mandatory for choosing the matched EBVCTLs [14].

Third-party EBV-CTLs were tested for the first time by Haque et al in a phase 2 trial [15]. 33 patients were enrolled (31 with PTLD after SOT and 2 after allo-SCT). At this time, the EBV-CTLs administered were only partially HLA matched. At six months the ORR resulted in 51.5% (14 complete responses [CR] and 3 partial responses [PR]) and two cases of relapse were reported during the follow-up of 1–7.5 years. Subsequently, other Groups reported similar outcomes and low toxicity with EBV-CTLs, particularly in the incidence of GvHD [16,17]. In December 2002, the European commission approved tabeleucleucel (Ebvallo®), the first allogeneic off-the-shelf EBV-specific T-cell for the treatment of R/R PTLD after a prior line of therapy. With this authorization, the ALLELE trial, a multicenter phase 3 trial (NCT03394365), was conducted and enrolled R/R EBV-PTLD post-SOT (N=29) and post-allo-SCT (N=14) [18]. In this trial, the choice of tabeleucleucel lot depended on specific patient HLA. Each patients received tabeleucleucel intravenously at 2 x106 cells per kg on days 1, 8 and 15 in 35-day cycles. The primary endpoint was ORR. Overall, 22 (51%) patients were responders with a median follow-up of 11 months (2.6-19.8). The median duration of response (DOR) were 23 months. Disease progression resulted in the most common adverse event and occurred in 4/14 (29%) of allo-SCT cases and 8/29 (14%) of the SOT group. More recently, an update of the ALLELE study, presented at ASH 2024 in San Diego, reported the results of a cohort of 75 patients (49 post-SOT and 26 post-alloSCT), confirming the previous results. This update demonstrated an ORR of 50.7%, a DOR of approximately 23 months, and a median OS of 18.4 months [19]. Indeed, a subsequent study by Barlev et compared the group of 30 patients (n= 14 allo-SCT and 16 SOT) enrolled and treated in the ALLELE trial with 84 patients (36 allo-SCT and 48 SOT) treated according to standard treatment and derived from a real-world study called RS002 [20]. The results were consistent with the pivotal trial demonstrated an advantage of tabelecleucel compared with standard treated group. Overall, these findings are encouraging for the potential inclusion of tabelecleucel in the therapeutic algorithm for R/R EBV-PTLD. Even more surprising, although still preliminary, results have been obtained from the use of EBVallo in the setting of patients with PTLD and central nervous system involvement. A study of 18 patients reported ab ORR was 77.8% (14/18), with a best overall response of CR (38.9%; n=7) or PR (38.9%; n=7) Median time to response was 1.8 months (range 0.7–6.4). Overall, 1-year and 2-year OS rates were 70.6% and 54.9% and both 1-year and 2-year OS rates were higher in responders (85.7% and 66.7%, respectively) vs non-responders (0% and 0%, respectively). A phase 2 trial (EBVision-ATA129-EBV-205-) is ongoing to evaluate the efficacy of tabelecleucel in patients with EBV+ diseases, CNS EBV+ PTLD [21].

Over the past decade, CAR-T cells have revolutionized the treatment of certain B-cell lymphoid malignancies expressing CD19. Since PTLD is most often a B-cell lymphoma, CAR-T cells have been applied in resistant cases, yielding interesting results [8]. One of the most promising applications of CAR-T in the PTLD treatment is in the setting of SOT being EBV negative in more than half of cases. A recent real-world retrospective study analyzed the outcome of 22 R/R SOT-PTLD treated with CAR-T [22]. The 2-year progression free survival and OS resulted in 35% and 48% respectively. 18/22 (82%) experienced cytokine release syndrome (CRS) but only one presented CRS grade 3-4. Three patients showed allograft rejection. Overall, these results were consistent with those known for the treatment of B-cell lymphomas.

In conclusion, PTLD is a rare but highly aggressive disease associated with poor outcome. In the refractory cases EBVrelated, cellular therapy with tabelecleucel achieved a growing level of evidence which will lead to the standard in the secondline treatment. CAR-T cells represent a valid option, particularly for EBV-negative cases, although many manufacturer limitations including the time of production are still to be solved.

Not applicable.

M.C. conceived and wrote the manuscript of this mini-review. PdF revised and corrected the manuscript. The authors read and approved the final manuscript.

This work did not receive funding.

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