Foe to Ally: Oncolytic Virus-Driven Xenorejection Ignites Potent Antitumor Immunity

Abstract

In a groundbreaking study published in the journal Cell, Yongxiang Zhao and collaborators designed a recombinant oncolytic virus (NDV-GT) by introducing the porcine α1,3-galactosyltransferase (α1,3GT) gene into the Newcastle disease virus (NDV). The engineered virus specifically infects tumor cells to express immunogenic αGal epitopes, thereby leveraging xenogeneic rejection mechanisms to activate robust antitumor immune responses (Figure 1) [1]. The innovative oncolytic virus demonstrates significant safety and preliminary efficacy in a cynomolgus monkey liver cancer model and a clinical trial enrolling 20 patients with refractory cancers.

Oncolytic viruses (OVs) have emerged as a promising and versatile therapeutic modality in cancer immunotherapy, owing to their ability for selective oncolysis and induction of systemic antitumor immunity [2]. However, inadequate immune priming, limited intra-tumoral dissemination and propagation, and rapid neutralization significantly hinder their therapeutic efficacy and clinical translation [3]. Moreover, the immunosuppressive tumor microenvironment (TME) markedly suppresses the outcomes of OV-based treatments. Despite advancements in engineered OVs and combinatorial regimens designed to enhance immune activation, clinical response rates remain unsatisfactory, indicating the urgent need for innovative strategies [4].

Xenogeneic rejection is a hyperacute immune response that occurs when heterologous organs or tissues are transplanted into a recipient of another species. The robust rejection could rapidly destroy xenografts by complement activation and endothelial damage [5]. The αGal epitope, a unique carbohydrate antigen, is widely present in non-primate mammals (e.g., pigs) and New World monkeys. However, during evolution, the ancestors of Old World monkeys and humans lost the αGal epitopes due to genetic mutations, but evolved anti-Gal antibodies to recognize the epitopes. Thus, when the organs or tissues from non-primate mammals are transplanted into humans, the anti-Gal antibodies quickly bind to αGal epitopes of xenografts, activating hyperacute rejection. Inspired by the hyperacute xenogeneic rejection, a porcine antigen was integrated into the Newcastle disease virus (NDV-GT) to deliver xenogeneic αGal epitopes to tumor cells (Figure 1A). Such recombinant virus camouflages porcine antigens on malignant cells, which would be recognized by the human body as heterologous transplant organs, thereby eliciting tumor-targeted hyperacute rejection analogous to xenograft destruction and converting the “cold” immunosuppressive TME to “hot” (Figure 1B).

The NDV-GT virus specifically and effectively infected different types of cancer cells in vitro as well as the parent virus, while exhibiting minimal infection in noncancerous cells. Moreover, the infected cancer cells effectively expressed the exogenous gene (α1,3GT), suggesting that NDV-GT can target tumor cells and mask them with porcine antigens. Interestingly, the αGal engineering significantly enhanced the oncolytic activity of NDV-GT for directly killing cancer cells.

To study the antitumor effects in vivo, a primary liver cancer model was established in cynomolgus monkeys, which were then intravenously administered with NDV-GT. Of note, the tumors in the monkeys receiving NDV-GT were completely eliminated 3-month posttreatment, while NDV treatments only delayed the tumor growth. The effective antitumor effects of NDV-GT are attributed to the following mechanisms: (1) the specific infection for tumor cells directly induces oncolysis; (2) the engineered virus selectively decorates αGal on tumor cells triggers hyperacute rejection through the activation of complement cascades; (3) NDV-GT disrupts tumor vasculature by inducing thrombi formation, leading to ischemic necrosis; (4) NDV-GT activates the antitumor immune responses: NDV-GT infects tumor cells to express αGal which could be recognized by anti-Gal antibodies, triggering antibody-dependent cellular cytotoxicity (ADCC) to eliminate cancer cells. The released αGal and tumor antigens would be processed by antigen-presenting cells (APCs) to activate CD4⁺/CD8⁺ T cells, and αGal could enhance T cell differentiation and activation. Moreover, the inflammatory signals and chemokines recruit T cell infiltration to promote antitumor immunity. These coordinated actions drive complete tumor elimination by NDV-GT. Importantly, NDV-GT demonstrated great biocompatibility in cynomolgus monkeys, supporting its translation potential for the treatment of human cancers.

Finally, the engineered virus was utilized to treat 20 patients with refractory and metastatic cancers in an interventional clinical trial. Impressively, 90% of patients with different types of tumors achieved disease control, and a cervical cancer patient even got complete remission. In a representative case of metastatic ovarian cancer (Patient P2), NDV-GT actively replicated in tumor tissue and induced substantial αGal expression posttreatment, demonstrating that the recombinant virus can reprogram human cancer cells with xenotransplantation-like markers to activate hyperacute rejection. Furthermore, NDV-GT treatment could remodel the TME by promoting T lymphocyte infiltration, activating tumor-specific adaptive immunity, and disrupting immunosuppressive networks, thereby potentiating antitumor responses. Thus, NDV-GT treatment effectively suppressed the tumor progression in patients with refractory cancers regardless of organs or types. Meanwhile, NDV-GT demonstrated great biosafety and maintained the levels of anti-NDV antibodies within the normal ranges. These encouraging results suggest that NDV-GT can be effectively and safely utilized in the treatment of refractory tumors, regardless of tumor type, and support its clinical feasibility.

In summary, the authors integrate a porcine-derived gene (α1,3GT) into the oncolytic Newcastle disease virus to obtain a recombinant NDV-GT. By exploiting the selective infection effect toward tumor cells, NDV-GT effectively tags the porcine-specific antigens (αGal) onto tumor cell membranes, driving the immune system to recognize tumors as “xenogeneic grafts.” This innovative manipulation ingeniously repurposes xenogeneic rejection, a clinically adverse process associated with graft failure in transplantation, to reprogram tumors into immunologically hostile xenografts, thereby activating hyperacute rejection. This study not only presents a pioneering strategy that employs xenogeneic antigens to harness pre-existing natural antibodies, thereby enhancing the immunotherapeutic efficacy of oncolytic viruses against refractory tumors, but also establishes an innovative conceptual framework for advancing oncolytic virus and tumor vaccine development. Since anti-Gal antibodies are widely present in humans, the αGal-based xenorejection strategy would offer a universal and effective solution for activating the antitumor responses. Although this study achieves a promising OV platform, there are still several limitations: (1) the small clinical cohort and short follow-up limits the long-term safety and efficacy assessment, (2) the immunosuppressive TMEs might inhibit the therapeutic effect, (3) infection escape of tumors would impair the hyperacute rejection and may induce recurrence. Thus, future efforts should focus on the following directions: (1) optimizing tumor-specific targeting efficacy to circumvent infection resistance; (2) amplifying direct oncolysis and immunogenicity, and discovering the mechanisms; (3) conducting multicenter clinical studies (phase II/III) across diverse cancers to establish efficacy benchmarks, organ-specific responses, and long-term safety profiles, (4) developing rational combination therapeutic strategies, such as integrating with immune checkpoint inhibitors or radiotherapy, to maximize immune activation. Moreover, the concept of xenogeneic rejection could be innovatively repurposed for diverse therapeutic applications, such as vaccine engineering (functionalizing vaccine with αGal epitopes to enhance its immunogenicity), and precision nanomedicine (αGal-decorated drug carriers leverage anti-Gal antibodies to enhance targeted delivery to APCs).

Yanglin Xu: conceptualization (lead), writing – original draft (lead). Bingcheng Chang: funding acquisition (equal), software (equal), writing – review and editing (equal). Wei He: funding acquisition (equal), software (equal), and writing – review and editing (equal). Jia Liu: conceptualization (lead), funding acquisition (lead), supervision (lead), and writing – review and editing (lead). All authors have read and approved the final manuscript.

The authors have nothing to report.

The authors declare no conflicts of interest.