Neoadjuvant chemo-immunotherapy in a kidney transplant recipient with locally advanced non-small cell lung cancer: a case report of a therapeutic dilemma

Introduction

Background

Immune checkpoint inhibitors (ICIs) have become a cornerstone in the management of locally advanced non-small cell lung cancer (NSCLC), improving both response rates and survival (1).

Rationale and knowledge gap

However, solid organ transplant recipients are excluded from clinical trials because of the high risk of immune-mediated allograft rejection. Evidence regarding the safety and efficacy of ICIs in kidney transplant recipients remains scarce and mainly limited to retrospective studies (2-4).

Objective

We report a rare case of a renal transplant recipient with resectable locally advanced squamous NSCLC successfully treated with neoadjuvant chemo-immunotherapy, illustrating a potential balance between oncologic efficacy and graft preservation. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1482/rc).

Case presentation

A 69-year-old man with a medical history notable for stage I chronic obstructive pulmonary disease and a kidney transplant in 2012 for end-stage renal disease of unknown aetiology was referred for evaluation of newly detected pulmonary masses. Patient reported a 35-year history of tobacco use (estimated at approximately 20 pack-years, 1975–2010) and had a history of occupational exposure to asbestos during 6 years in the automotive maintenance sector. The patient had a low immunological risk profile, with no prior human leukocyte antigen (HLA) sensitization and no detectable donor-specific antibodies. HLA mismatch included one class I and two class II mismatches. Induction therapy consisted of an anti-interleukin-2 (IL-2) receptor antibody, followed by maintenance immunosuppression with cyclosporine, mycophenolate mofetil, and corticosteroids. At 3 months after transplantation, a subclinical acute cellular rejection was detected on protocol biopsy and treated with methylprednisolone pulses, with a switch from cyclosporine to tacrolimus thereafter. His post-transplant immunosuppressive regimen included tacrolimus 3 mg daily and mycophenolate mofetil, combined with prophylactic trimethoprim-sulfamethoxazole (TMP-SMX). Mycophenolate was discontinued in July 2024 following the diagnosis of NSCLC and replaced by oral prednisone (10 mg/day). Prophylaxis with TMP-SMX had been discontinued several months earlier, likely contributing to infection risk.

During his routine annual kidney graft surveillance, renal ultrasonography demonstrated a 13-cm transplanted kidney in the right iliac fossa with preserved cortical architecture, homogeneous vascularization, patent hilar vessels, and no evidence of pelvicalyceal dilation. Native kidneys were reported as atrophic. Concurrent chest radiography revealed two left-sided opacities, subsequently confirmed on contrast-enhanced thoraco-abdomino-pelvic computed tomography (CT) scan: a 70 mm × 58 mm mass in the superior segment of the left lower lobe, and a 27 mm × 28 mm para-aortic mass in the left upper lobe abutting mediastinal fat. F-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)-CT did not reveal distant metastases (Figure 1).

Figure 1 Discovery and pre-treatment assessment. (A) Frontal chest X-ray showing spiculated masses in the left upper and lower lobes. (B) Axial chest CT demonstrating a 27 mm spiculated mass of the left upper lobe. (C) Axial chest CT demonstrating a 70 mm spiculated mass of the left lower lobe. (D) Sagittal chest CT confirming both spiculated lesions in the left upper and lower lobes. (E) ¹⁸F-FDG PET-CT showing a hypermetabolic spiculated mass of the left upper lobe (SUVmax 12.7). (F) ¹⁸F-FDG PET-CT showing a hypermetabolic spiculated mass of the left lower lobe (SUVmax 12.2). ¹⁸F-FDG, F-18 fluorodeoxyglucose; CT, computed tomography; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Bronchoscopic examination identified a necrotic endobronchial lesion in the left Nelson bronchus (Lb6); histopathology demonstrated squamous cell carcinoma (p40⁺, CK7⁻, TTF-1⁻), with tumor proportion score programmed death ligand-1 (PD-L1) at 15%. Molecular profiling was not performed given the histological subtype and smoking history. Brain magnetic resonance imaging (MRI) was normal. The disease was staged as cT4N0M0 [American Joint Committee on Cancer (AJCC) 8^th edition] and considered technically resectable. Baseline pulmonary function tests showed a forced expiratory volume in 1 second (FEV₁) of 2.87 L (85% predicted), forced vital capacity (FVC) of 4.85 L (105% predicted).

The case was discussed in a multidisciplinary tumor board. A definitive chemoradiotherapy (CRT) approach was deemed suboptimal due to the extensive radiation field required, which was expected to result in significant functional lung loss and inferior long-term survival. A neoadjuvant chemo-immunotherapy regimen—carboplatin [area under the curve (AUC) 5], paclitaxel (175 mg/m²), and nivolumab (360 mg) every 3 weeks for three cycles, followed by left pneumonectomy was selected, aiming for curative resection, reduced immunotherapy exposure, and potentially lower rejection risk compared to prolonged systemic treatment. Decision-making involved nephrology and transplant teams, who considered the risk of acute rejection leading to dialysis acceptable under close laboratory monitoring. Drug-drug interaction precautions were implemented regarding concomitant use of aprepitant and tacrolimus, with serial tacrolimus level assessments at baseline, during steady-state aprepitant exposure, and following its discontinuation.

The neoadjuvant regimen was initiated 5 weeks after the initial chest radiography. During cancer management, tacrolimus trough levels were maintained between 5–6 ng/mL, with levels of 6.6 ng/mL prior to ICI initiation and 4.5 ng/mL during treatment.

All cycles were well tolerated without the need for dose reduction, with no deterioration in renal function and only grade I peripheral neuropathy attributable to paclitaxel. Renal function remained stable during treatment, with serum creatinine ranging from 115 µmol/L at baseline to 107 µmol/L at the end of chemo-immunotherapy. Proteinuria remained low and below the 500 mg/day threshold considered clinically significant in kidney transplant recipients, ranging from 111 mg/day at baseline to 218 mg/day during treatment. An interim evaluation with contrast-enhanced thoraco-abdomino-pelvic CT scan after two cycles demonstrated a decrease in the largest diameter of the left lower lobe mass to 59 mm (previously 70 mm) and of the spiculated left upper lobe lesion to 23 mm (previously 25 mm), with overall stable anatomical relationships. No new suspicious lesions were identified. The sum of target lesions decreased from 95 mm to 82 mm (−14%), corresponding to stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (Figure 2).

Figure 2 Radiological evaluation under neoadjuvant chemo-immunotherapy. (A) Baseline axial chest CT showing a 70 mm × 58 mm spiculated mass in the superior segment of the left lower lobe. (B) Post-treatment axial chest CT showing reduction of the same lesion to 59 mm × 52 mm after three cycles of chemo-immunotherapy. (C) Baseline axial chest CT showing a 27 mm × 28 mm para-aortic spiculated mass in the left upper lobe. (D) Post-treatment axial chest CT showing decrease of the para-aortic lesion to 25 mm × 20 mm after chemo-immunotherapy. CT, computed tomography.

The patient subsequently underwent left pneumonectomy 3 weeks after completion of the last neoadjuvant cycle, without major perioperative complications, except for postoperative dysphonia secondary to recurrent laryngeal nerve palsy. Histopathological analysis of the surgical specimen revealed >90% viable tumor cells with minimal necrosis in the upper lobe lesion, consistent with no pathological response (non-MPR), and a major pathological response (<10% residual viable tumor cells) in the lower lobe lesion. The final pathological stage was ypT4N0 pN0 V0 L0 PL0 R0 (AJCC 8^th edition) (Figure 3).

Figure 3 Histopathological findings from surgical lung specimens after neoadjuvant chemo-immunotherapy. (A) H&E staining at ×20 magnification of the upper lobe showing lymphocytic infiltrate (yellow asterisk) and carcinoma foci (red asterisk). (B) H&E staining at ×10 magnification of the upper lobe showing lymphocytic infiltrate (yellow asterisk) associated with multiple carcinoma foci (red asterisk). (C) H&E staining at ×10 magnification of the upper lobe showing viable tumor foci (red asterisk) with stromal fibrosis (blue circle). (D) H&E staining at ×10 magnification of the upper lobe showing viable tumor cells (green circle), lymphocytic infiltrate (yellow asterisk), and necrotic areas (brown square). (E) H&E staining at ×5 magnification of the lower lobe showing a small residual tumor focus (red asterisk). (F) Immunohistochemical staining for p40 confirming residual tumor cells in the lower lobe (magnification: ×5). (G) H&E staining at ×40 magnification of the lower lobe highlighting residual viable carcinoma (red asterisk). (H) H&E staining at ×5 magnification showing multiple lymphoid aggregates (blue arrows) consistent with immunotherapy-related immune activation. (I) H&E staining at ×20 magnification of the lower lobe showing tertiary lymphoid stromal reaction with foamy macrophages (yellow circle). (J) H&E staining at ×10 magnification of the lower lobe showing marked stromal reaction and focal fibrotic remodeling (yellow arrows). H&E, hematoxylin and eosin.

Postoperative follow-up included surveillance imaging and renal function monitoring. At 3 months, there was no evidence of recurrence or renal allograft rejection. However, the patient died 5 months after surgery from Pneumocystis jirovecii pneumonia (PJP) affecting the remaining lung, despite targeted antimicrobial therapy with TMP-SMX, and high-flow nasal oxygen therapy, and without histological evidence of transplant rejection (Figure 4).

Figure 4 Chronological timeline of patient management. Schematic overview summarizing the key steps from diagnosis to outcome, including diagnostic imaging (chest X-ray, CT, and PET-CT), initiation and completion of neoadjuvant chemo-immunotherapy, surgery (left pneumonectomy), postoperative follow-up, and the occurrence of Pneumocystis jirovecii pneumonia 5 months after resection. CT, computed tomography; MTB, multidisciplinary tumor board; PET, positron emission tomography.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki and its subsequent amendments. Publication of this case report and accompanying images was waived from patient consent according to the institutional review board of CHU Reims. The French National Commission approved access to patient data for this retrospective report for Data Protection (CNIL, No. 2049775 v0) under registration number MR004020820243.

Discussion

The management of locally advanced NSCLC has undergone a major transformation over the past decade. Historically, operable stage IIIA patients underwent surgery, sometimes preceded or followed by platinum-based chemotherapy, with modest overall survival (OS) results (5). For inoperable patients, concurrent CRT was the standard of care, with a median OS of around 28–30 months (6).

Immunotherapies, particularly ICIs, have revolutionized these standards. The CheckMate-816 trial (1) demonstrated that a combination of nivolumab and neoadjuvant chemotherapy achieved a pathological complete response in 24% of cases, compared with only 2% for chemotherapy alone, and improved event-free survival. The KEYNOTE-671 (7) and AEGEAN (8) studies confirmed these results. In parallel, the PACIFIC trial (6) established CRT followed by 1 year of durvalumab as the standard for inoperable cases, with a median OS exceeding 47 months. These results confirm ICI as a cornerstone of locally advanced-stage treatment. However, efficacy must be weighed against toxicity, particularly in frail populations such as solid-organ transplant recipients.

Platinum doublets (cisplatin or carboplatin + paclitaxel or pemetrexed) remain the backbone of NSCLC therapy; their toxicities (hematologic, gastrointestinal, neurologic) are mostly reversible and do not directly affect graft tolerance. In contrast, ICIs expose patients to a broad spectrum of immune-related adverse events involving the skin, gut, lung, or endocrine organs (9). In transplant recipients, the key concern is immune tolerance breakdown leading to acute, often irreversible rejection. Kidney transplantation requires a fragile equilibrium between immunosuppression (to prevent rejection) and residual immune competence (to fight infections and cancer). Transplant recipients have a 2- to 3-fold increased cancer risk, notably for skin tumors and lymphomas (10); immunosuppression type, dose, and duration are major determinants and also predispose to severe opportunistic infections (11). Therefore, any therapeutic change must preserve graft function while minimizing immune escape (12). This immunosuppression, however, directly conflicts with the principle of ICIs, which restore antitumor immunity at the cost of graft tolerance loss. In kidney-transplant patients, reported acute-rejection rates range between 25% and 45%, with graft loss in 20 to 30% (2-4,13). In the systematic review by Manohar et al. (2), acute rejection occurred in 41% of cases, usually within 24 days. The multicenter study by Murakami et al. (3) reported similar findings, while the INNOVATED cohort (4) suggested a lower rejection rate (26%) with tighter selection and multidisciplinary coordination. Despite this, graft preservation remains unpredictable.

Beyond alloimmune rejection, ICIs may also trigger acute kidney injury (AKI) through various mechanisms, including acute interstitial nephritis, glomerulopathies, and tubular injury, complicating interpretation of creatinine elevations in this population. Distinguishing rejection from ICI-related nephrotoxicity often requires renal biopsy, a procedure with potential risk in immunosuppressed patients. In this context, maintaining low-dose corticosteroids may represent a reasonable compromise, limiting rejection risk without significantly impairing ICI efficacy, since the detrimental impact of steroids appears more pronounced when used before ICI initiation rather than as treatment for immune-mediated toxicity (14).

Faced with this dilemma, we favoured short-course (three-cycle) neoadjuvant chemo-ICI rather than surgery with adjuvant chemotherapy alone (poor prognosis under immunosuppression) or CRT followed by 1 year of durvalumab. Limiting ICI exposure to preoperative cycles theoretically reduces cumulative rejection risk while preserving the potential for pathological response, a strong surrogate for OS. It also avoids large radiation fields and associated pulmonary function loss, crucial in comorbid patients. Treatment was well tolerated, renal function remained stable, and curative R0 resection was achieved. Histopathology revealed a dissociated response between two tumor sites (Figure 3), consistent with potential spatial tumor-immune heterogeneity under ICI pressure.

Remarkably, no graft rejection occurred despite nivolumab exposure and reduced immunosuppression. This observation may suggest that short-term ICI exposure in the neoadjuvant setting can be tolerated under close immunologic monitoring. More recently, prospective data from the CONTRAC study have proposed a standardized strategy consisting of conversion to a mechanistic target of rapamycin (mTOR) inhibitor combined with pulsed corticosteroids around each ICI cycle. In this phase I trial of kidney transplant recipients treated with PD-1 blockade, this approach resulted in antitumor responses without any kidney allograft rejection events and is now emerging as a reference strategy to mitigate rejection risk in this clinical setting. (15)

The patient’s subsequent death from PJP (Figure 4) highlights another major risk in this population: opportunistic infection related to chronic immunosuppression, which may surpass rejection as a cause of mortality (16,17). This includes PJP, viral and invasive fungal infections, which remain major contributors to morbidity and mortality among kidney-transplant recipients (17,18). Prophylaxis with TMP-SMX had been discontinued several months earlier, likely contributing to infection risk, and in accordance with routine post-transplant follow-up once the early post-transplant period had elapsed. At the time of oncologic management, the patient was no longer receiving mycophenolate mofetil but presented persistent lymphopenia, which may have increased susceptibility to opportunistic infection in the context of chemotherapy and corticosteroid exposure. These observations are consistent with reports of Pneumocystis jirovecii in kidney-transplant recipients receiving belatacept, a T-cell costimulation blocker that modulates adaptive immune responses. Opportunistic infections have been described in this context, particularly in patients with additional risk factors such as lymphopenia (19). These observations emphasize the need to maintain systematic PJP prophylaxis when initiating ICI therapy in this high-risk population.

This case illustrates that short-course neoadjuvant ICI exposure can represent a feasible compromise, provided strict nephrology-oncology coordination, drug-interaction monitoring (e.g., aprepitant-tacrolimus), and reinforced infection prophylaxis. Future registry studies should identify predictive factors of tolerance, explore mTOR-based strategies (15), clarify the impact of corticosteroid use (14), and delineate safe perioperative ICI durations for transplant recipients.

Conclusions

In kidney transplant recipients with locally advanced NSCLC, treatment decisions are very difficult to make and require a careful balance between oncological benefits and the risk of graft loss. Neoadjuvant chemo-immunotherapy followed by surgery may be a reasonable compromise, provided that decisions are made in a multidisciplinary consultation with the advice of a nephrologist and that the patient is clearly informed. It is essential to report these rare cases in order to guide future practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1482/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1482/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1482/coif). A.D. reports payment or honoraria from MSD for a paid presentation at a medical meeting, and congress invitations from AstraZeneca and Kyowa, outside of the submitted work. M.D. reports payment or honoraria for lectures or presentations from AstraZeneca, Roche, Bristol-Myers Squibb, MSD, Sanofi, Pfizer, Amgen and J&J outside of the submitted work. G.D. reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Chiesi, Sanofi, GSK (personal fees), outside of the submitted work. J.A. reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Pfizer, MSD, Bristol-Myers Squibb, Novartis, AstraZeneca, Takeda, Sanofi, J&J and AMGEN; support for attending meetings and/or travel from Roche, Pfizer, MSD, Takeda and Sanofi; and Grants from AMGEN, French Innovative Research Fund outside of the submitted work. The other authors have no 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. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki and its subsequent amendments. Publication of this case report and accompanying images was waived from patient consent according to the institutional review board of CHU Reims. The French National Commission approved access to patient data for this retrospective report for Data Protection (CNIL, No. 2049775 v0) under registration number MR004020820243.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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