Complete Remission of Hepatocellular Carcinoma With Atezolizumab and Bevacizumab Following Prior B-cell Depletion.

CASE REPORT
A patient in their 70s with a history of resolved hepatitis B virus (HBV) infection and no history of alcohol consumption presented to our hospital on March 31st, 2023, with complaints of sudden-onset diffuse abdominal pain and near-syncope that had persisted for several hours. The medical history was significant for papillary urothelial carcinoma of the bladder, diagnosed 7 years prior, for which the patient had undergone multiple transurethral resections of bladder tumors (TURBT).
Upon admission, an abdominal CT scan revealed liver cirrhosis and a suspected hepatocellular carcinoma (HCC), complicated by tumor rupture and associated hemoperitoneum (Fig. 1A). Given the patient’s critical condition, emergent transcatheter arterial embolization (TAE) was performed to control the bleeding.
A chest CT scan, conducted as part of the work-up, revealed enlarged left axillary lymph nodes. Due to the rare incidence of HCC metastasis to axillary lymph nodes, an incisional biopsy was performed. Pathologic analysis identified diffuse large B-cell lymphoma (DLBCL), which was confirmed through a bone marrow biopsy and PET/CT scan, classifying the DLBCL as Ann Arbor stage I (Fig. 1D).
Further evaluation with a CT-guided liver biopsy confirmed the liver tumor as HCC. Given the dual cancer diagnoses, priority was given to managing HCC due to its immediate threat to the patient’s health. The patient subsequently underwent an open hepatectomy, along with a cholecystectomy to remove the tumor. The final pathologic assessment revealed stage III HCC (tumor stage ypT4), classified under Barcelona Clinic Liver Cancer (BCLC) stage A.
Following recovery from surgery, the patient began treatment for DLBCL, receiving 5 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) between May and September 2023. An interim PET/CT scan in August 2023 revealed a complete metabolic response of the lymphoma (Fig. 1F); however, a hypermetabolic focus was identified in the surgical bed of the liver. Subsequent liver MRI confirmed HCC recurrence, and the patient’s AFP levels increased to 746 ng/mL (Fig. 1B). A second TACE was performed, and the patient completed the 6th cycle of R-CHOP by November 2023. Despite treatment, AFP levels continued to rise (3001 ng/mL), and recurrent tumors in the paracaval region of the liver were confirmed as HCC recurrence via CT-guided biopsy (Fig. 1C).
Thereafter, the patient started 1st-line standard immunotherapy with atezolizumab (1200 mg, IVA) and bevacizumab (15 mg/kg, IVA) in January 2024. After the first cycle, the AFP levels had a remarkable drop from 5704 to 3423 ng/mL, and grade 3 neutropenia was observed, leading to a 6-week postponement of the second cycle. After 3 cycles of atezolizumab plus bevacizumab, the patient’s AFP declined to normal range (3 ng/mL). The patient continued the monthly ate-bev treatment, with AFP level remaining within normal range and liver CT in July 2024 confirmed complete tumor remission according to RECIST 1.1 criteria (Fig. 1D).
Due to lymphoma treatment, lymphocytes and IgG/A/M levels were monitored, revealing B-cell depletion and hypogammaglobulinemia following R-CHOP therapy (Figs. 2A, B, C). It is interesting to note that the percentage of NK cells increased after atezolizumab-bevacizumab treatment (Fig. 2A). In addition, AFP levels throughout the entire treatment course are illustrated (Fig. 2D).

DISCUSSION
Rituximab, as part of the R-CHOP regimen, effectively targets CD20+ B cells, leading to sustained B-cell depletion. Despite this depletion, anti-PD-1 therapies, primarily designed to reactivate T-cell functions, may still be effective. This case suggests that prior B-cell depletion does not preclude a successful immune response with anti-PD-1 therapy, as T cells remain responsive to immune checkpoint inhibition. Several studies indicate that the combination of PD-1 inhibitors and rituximab appears to maintain efficacy in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) without compromising safety. In a phase II study by Westin et al,4 the combination of the PD-1 inhibitor CT-011 and rituximab achieved an objective response rate (ORR) of 66% and a complete response (CR) rate of 52% in patients with relapsed follicular lymphoma, without severe toxicities, suggesting enhanced clinical efficacy from both innate and adaptive immune mechanisms. In Qin et al‘s5 single-center study, a similar regimen in diffuse large B-cell lymphoma (DLBCL) showed an ORR of 52.8%, with a median progression-free survival (PFS) of 2.8 months and overall survival (OS) of 19.6 months, and only rare occurrences of grade 3 or 4 adverse events. A meta-analysis by Guan et al6 further supports the safety and efficacy of PD-1/PD-L1 inhibitors in NHL, highlighting that combination immunotherapy with chemotherapy enhances ORR (65%) and CR rates (41%) compared with monotherapy, with manageable side effects. These findings suggest that rituximab, a B-cell depleting agent, does not adversely affect the efficacy of anti-PD-1 therapy, supporting the finding of this case.
In addition, NK cells play a critical role in antitumor immunity by directly targeting cancer cells and supporting other immune effector cells. Hsu and colleagues demonstrated a mouse tumor model that NK-cell activation was largely elicited by PD-1 blockade. The suppression of tumor growth was assured contributed to NK-cell rather than T-cell-mediated cytotoxic effect by NK-cell depletion and T-cell depletion, respectively, regardless of PD-1 administration.7 In different cancer lines, functional impairment of NK cells in B-CLL was also observed with decreased activating receptors and cytokines secretion when PD-1 was presented, which could be partially reversed by anti-PD-1/PD-L blockade.8 A similar result was also seen in nasopharyngeal carcinoma, as an additional anti-PD-1 antibody shown increasing NK-cell cytotoxicity towards NPC cells.9 In the context of HCC, a narrative review by Wang and colleagues indicated that marked decreased infiltration of NK cells in HCC was found along with reduced activity, production of cytokines such as TNF-α and IFN-γ and cytolytic granules. Expression of immune checkpoints negatively regulated NK-cell responses to HCC.10 Anti-PD-1 therapy has been shown to potentiate NK-cell activity, thus enhancing the cytotoxic response against cancer cells.
In this case, the observed increase in NK-cell percentage following treatment with atezolizumab and bevacizumab may indicate a robust immune activation, contributing to the patient’s complete response. Research in HCC treatment supports the involvement of NK cells as key players in antitumor activity, with checkpoint inhibitors facilitating NK-cell-mediated cytotoxicity. Further studies on NK-cell activity in response to anti-PD-1 therapy in HCC could illuminate mechanisms that improve outcomes for patients with complex immunologic backgrounds, as seen in this case. Multiple trials as immunotherapeutic antibodies targeting NK cells and chimeric antigen receptor NK-cell therapy were ongoing.
After initiation of atezolizumab and bevacizumab, we had discovered a decreasing trend of CD8+ T cells on our patient. This finding is consistent to the findings from Wang and colleagues, which significant decreasing of peripheral CD8+ T cells was measured effective group and no significant CD8+ T cells drop was found in ineffective group in gastric cancer treated with PD-1 inhibitor. This may imply the migration of specific T cells to tumor sites.11

However, there are still limitations from this case report. First, scarce report of lymphodepletion therapy before immunotherapy was documented and was not widely discussed. We need more experience for better knowledge and assessment. Moreover, still debating results of whether peripheral T cells subset correlates to effectiveness of immunotherapy was discussed. Further comprehensive study should be conducted for concrete results.
In conclusion, this case highlights that prior B-cell depletion with rituximab does not hinder the efficacy of anti-PD(L)-1 therapy, indicating that T cells remain responsive to immune checkpoint inhibition. The observed increase in NK cells following atezolizumab and bevacizumab treatment in HCC suggests a potential role for NK cells in enhancing antitumor responses.