Allogeneic Natural Killer Cells: An Additional Player in Human Immunodeficiency Virus Cure Approaches?
Year: 2024
Type: editorial
Abstract: (See the Major Article by Miller et al. on pages 1256–65.) Antiretroviral therapy (ART) targeting human immunodeficiency virus (HIV) has saved millions of lives. If ART is initiated early in infection, people with HIV (PWH) might have a close to normal life expectancy. Despite these spectacular advances in ART drug development and deliveries, there is still no vaccine or cure available after 40 years of intensive HIV research. A major obstacle for an HIV cure is the viral reservoir that persists in the body even following efficient and long-term ART. The principal goal of HIV cure strategies is therefore to identify and kill the rare cells that harbor integrated HIV proviruses and from where HIV can rebound, similar to cancer cure strategies aimed at identifying and killing in the most efficient way residual cancer cells. As ART, however, safely protects PWH from developing AIDS, any HIV cure strategy must prioritize safety. Adoptive immunotherapies have emerged as a potent approach in cancer treatments, and are also employed in the treatment of viral diseases for which no effective antiviral drugs are available, such as Epstein-Barr virus and cytomegalovirus infection. In this issue of The Journal of Infectious Diseases, Miller et al [1] report the results of a study that evaluated the safety of adoptive natural killer (NK) cell therapies in ART-treated, virologically fully suppressed PWH. Immunotherapy consisted of the infusion of haploidentical related donor NK cells in 6 individuals, supported by either interleukin 2 (IL-2) in 2 individuals or interleukin 15 (IL-15) in 4 individuals. Since IL-15 stimulation is more efficient when coupled to its receptor, the IL-15 injected corresponded to the N-803 superagonist, a heterodimer of IL-15 and its receptor, IL-15Rα [2]. IL-2 and IL-15 were used to stimulate NK cells overnight in vitro before infusion, and in vivo through, respectively, 6 and 3 injections of IL-2 and IL-15 starting 4 hours after the single NK cell infusion. Through frequent peripheral blood collections, and also lymph node and intestinal biopsies before and after immunotherapy, the authors show that the infused NK cells persisted for at least 1 week after infusion, and thereby similarly long as reported for cancer trials, even in the absence of pretreatment lymphodepleting chemotherapy generally used to “make space” for allogeneic cells. Donor NK cells were furthermore detected at day 28 posttransfusion in both lymph node and gut samples analyzed from 1 individual, providing promising data for adoptive NK cell therapies in PWH. The primary objective of this single-site pilot study was to determine the safety of adoptive transfer of haploidentical NK cells in PWH who are on fully suppressive ART, and the results from this small study, using either IL-2 or IL-15 in combination with NK cells, are encouraging, reporting largely grade 1 or 2 adverse effects (AEs) previously associated with cytokine treatments in PWH [3]. In particular, there were no signs or reported symptoms associated with cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). There were, however, two grade 3 toxicities reported in the study, with a low estimated glomerular filtration rate in 1 of the participants receiving IL-2 and low absolute lymphocyte count in 1 of the participants receiving IL-15. Future studies might want to study if other cytokines also known to increase NK cell cytotoxicity, such as interleukin 21 [4], would induce fewer AEs. Important limitations of this study are the small number of participants, the lack of control arms including only NK cells or cytokines, and also the fact that monocytes made up to 70% of the injected cells. It therefore remains to be determined whether severe AEs occur in larger studies, and also whether monocytes, NK cells, and/or cytokines are mainly responsible for AEs observed. The secondary explorative objective of this study was to determine whether adoptive immunotherapies with NK cells were associated with a reduction in HIV type 1 (HIV-1) reservoirs. Viral RNA and DNA were longitudinally quantified using in situ hybridization in lymph nodes of 4 participants (3 receiving IL-15 and 1 IL-2). The results indicate a moderate (<1 log) but consistent decrease of viral RNA in lymph nodes in all 4 individuals. These results are encouraging, but need to be confirmed by a sufficiently powered larger study that also includes more detailed characterizations of the viral reservoir and of NK cell functions. Furthermore, due to the study design, it is unclear whether reductions in viral reservoirs observed in these 4 individuals were due to the administration of cytokines, the adoptive transfer of NK cells or monocytes, or both. Despite the above listed limitations, this clinical trial based on transfer of NK cells into PWH represents a milestone. Most immunotherapies tested to date in the context of HIV cure approaches exploit adaptive components of the immune system (CD8+ T cells, broadly neutralizing antibodies [bNAbs]), building on previous experiences in cancer or infectious disease immunotherapies using CD8+ T cells and antibodies. NK cell therapies have, however, gained increased interest for the treatment of cancers, and an increasing body of data suggests that NK cells might also represent potent effector cells for HIV cure strategies. Several strategies harnessing NK cells for HIV cure have already been tested in preclinical or clinical pilot trials or proposed based on in vitro data (Figure 1). Indeed, NK cells have the potential to migrate into major anatomical sanctuaries of HIV, such as B-cell follicles that harbor follicular helper T cells supporting residual HIV replication [5–7], and NK cells have been described as important immune correlates associated with HIV remission in several cases of posttreatment controllers [8, 9]. Mature NK cells also are very efficient in mediating antibody-dependent cellular cytotoxicity (ADCC) in the presence of bNAbs, indicating the potential of combined immunotherapies with NK cells and bNAbs [10] (Figure 1). Promising data on transfer of allogeneic NK cells have previously been obtained using a mouse model, demonstrating that administration of allogeneic human NK cells alone can reduce the number of HIV-1 variants rebounding from latency and delay viral rebound following ART interruption in ART-treated humanized mice infected with HIV [11]. Combined with a latency-reversing agent (SUW133), the infusion of allogeneic human NK cells during ART seemed to even have eliminated the HIV reservoir in a subset of these mice [11]. Given the results from these previous studies, and the encouraging results from the current study by Miller et al [1], adoptive transfer of NK cells as a component of HIV cure strategies might be advantageous in several aspects compared to adoptive T cells. Indeed, infusion of NK cells is associated with lower risk of GvHD and of CRS, as well as easier applicability for off-the-shelf usage due to less strict autologous HLA matching requirements than T cells. The study here might also inform cancer immunotherapies, since the infused NK cells persisted despite the absence of lymphodepleting chemotherapy. Currently tested or proposed strategies to harness natural killer cells in the context of HIV cure research. Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; bNAbs, broadly neutralizing antibodies; CAR, chimeric antigen receptor; HIV, human immunodeficiency virus; IFN, interferon; IL, interleukin; KIR, Killer cell Immunoglobulin like receptor; NK, natural killer; TLR, Toll-like receptor. While a potential reduction of viral reservoirs resulting from NK cell immunotherapies is encouraging, if confirmed in larger studies, the question still remains how to further decrease viral reservoirs in order to enable durable control of HIV. Future studies might want to determine whether consecutive NK cell infusions can further reduce viral reservoirs. To increase the impact on the viral reservoir, it might also be necessary to combine the treatment with latency reversal agents or, alternatively, to infuse NK cells at ART initiation, when more antigen is still around, and finally to combine NK cell immunotherapies with other approaches, such as with bNAbs to mediate ADCC (Figure 1). Another important open question regards the consequence of the cytokine treatment for the observed effects. It is still unclear if and how an optimal cytokine treatment to support allogeneic NK cells has to be administrated, as adequate control groups were missing in this pilot study. In xenogeneic mouse models of adoptive human NK cell transfer, infusion with IL-2 or IL-15 promoted in vivo persistence of NK cells for >1 month [12], while in humanized mice infected with HIV, cytokine support was not necessary to reduce HIV reservoirs [11]. On the other hand, a previous safety trial in humans suggested an impact of IL-15 (N-803) alone on the viral reservoir [3], highlighting the important role of adequate control groups. Finally, NK cells derived from different donors differ in their antiviral activity, depending for example on the KIR/HLA compound genotypes, and selection of donors encoding for protective NK cell receptor genotypes, such as KIR3DS1 [13], might enhance anti-HIV activities (Figure 1). Future studies will need to address these important variables to optimize immunotherapies using NK cells. Nonetheless, the current study represents a pioneering pilot study on transfer of allogeneic NK cells in PWH under ART, that shall open future avenues aimed at harnessing NK cells in the realm of HIV cure research and potentially for viral diseases at large.
Authors: Marcus Altfeld, Michaela Müller-Trutwin
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4390744059