Chimeric antigen receptor T-cell therapy and bispecific antibodies in the treatment of lymphoma for human immunodeficiency virus-infected patients: A systematic review

Abstract

Background:

Chimeric antigen receptor T-cell therapy has emerged as a highly effective treatment for relapsed and refractory lymphomas; however, its application in individuals with human immunodeficiency virus remains underexplored. People with human immunodeficiency virus face an increased risk of developing malignancies such as lymphoma, where standard chemotherapy often results in suboptimal responses and heightened toxicity.

Objective:

To review and synthesize current literature on the use of chimeric antigen receptor T-cell therapy and bispecific antibodies in human immunodeficiency virus-associated lymphoma, examining efficacy, safety, and potential barriers to implementation.

Methods:

A systematic review of the literature was conducted using PubMed. Included studies comprised clinical trials, cohort studies, case reports, and preclinical research published between January 2000 and September 2024. Search terms included “HIV,” “lymphoma,” “CAR T cell therapy,” “bispecific antibodies,” “immunotherapy,” and “HIV-associated lymphoma.”

Results:

Preliminary data suggest chimeric antigen receptor T-cell therapy is feasible in human immunodeficiency virus-positive patients, with response rates comparable to human immunodeficiency virus-negative populations and manageable adverse events, including cytokine release syndrome and neurotoxicity. Engineering chimeric antigen receptor T cells to target human immunodeficiency virus-infected cells is under investigation as a potential curative strategy. However, challenges such as immunosuppression, low antigen expression, and interactions with antiretroviral therapy complicate treatment. Bispecific antibodies have shown promise in hematologic malignancies, but data in people with human immunodeficiency virus remain limited due to trial exclusions.

Conclusion:

Early findings support the feasibility and potential efficacy of chimeric antigen receptor T-cell therapy in human immunodeficiency virus-associated lymphoma. Larger, controlled trials are needed to establish safety, optimize treatment strategies, and expand therapeutic options for people with human immunodeficiency virus.

Introduction

The advent of highly active antiretroviral therapy (HAART) has significantly prolonged the lives of patients with human immunodeficiency virus (HIV), transforming what was once a fatal diagnosis into a manageable chronic condition. Despite these therapies, these patients remain at an increased risk for developing various malignancies, with lymphoma being among the most prevalent and life-threatening. ¹ The pathogenesis of lymphoma in HIV-positive individuals involves chronic immune activation, persistent viral infection, and the direct oncogenic effects of HIV. ² While HAART has improved outcomes, the standard chemotherapy regimens used in lymphoma treatment often result in suboptimal responses and heightened toxicity in this vulnerable population. ³

In recent years, novel immunotherapeutic approaches have emerged, promising to revolutionize the treatment landscape for lymphomas. Among these, chimeric antigen receptor T-cell (CAR T) therapy and bispecific antibodies (BsAbs) have shown remarkable efficacy in relapsed and refractory lymphomas in the general population.^4,5 CAR T therapy involves the genetic modification of a patient’s own T cells to express a receptor specific to a tumor-associated antigen, leading to targeted and potent anti-tumor activity. ⁶ BsAbs, on the other hand, are engineered to simultaneously bind to a tumor cell and a cytotoxic T cell, thereby facilitating targeted cell-mediated cytotoxicity. ⁷

Despite these advances, the application of CAR T therapy and BsAbs in HIV-positive lymphoma patients remains underexplored. HIV infection presents unique challenges for immunotherapy, including the potential for viral reactivation, altered immune cell function, and the interplay between antiretroviral drugs and immunotherapeutic agents. ⁸ Furthermore, there is substantial evidence indicating that HIV-positive patients have historically been excluded from clinical trials for new cancer therapies. This exclusion has been particularly notable in trials involving immune checkpoint inhibitors (ICIs). A study analyzing cancer ICI trials from 2019 to 2020 found that 74.4% of these trials excluded people with HIV (PWH), with only 6.9% conditionally including them based on immune function, and 18.7% including or not specifying HIV status. ⁹

This literature review aims to synthesize the current knowledge on the use of CAR T therapy and BsAbs in treating lymphoma among HIV-positive patients. It will examine preclinical and clinical studies, focusing on efficacy outcomes, safety profiles, and the impact of HIV-related factors on treatment response. We will explore the biological mechanisms underlying the therapeutic effects and potential complications of these immunotherapies in the context of HIV-associated immunodeficiency.

Methods

A systematic review of the literature was conducted to assess the use of CAR T therapy and BsAbs in HIV-positive patients with lymphoma. The database used for this research was PubMed, including studies published between January 2000 and September 2024, focusing on clinical trials, cohort studies, case series, preclinical research, and review articles. The search terms used were “HIV,” “lymphoma,” “CAR T cell therapy,” “bispecific antibodies,” “immunotherapy,” “malignancies,” and “HIV-associated lymphoma.”

The inclusion criteria were studies reported on the efficacy/safety of CAR T therapy or BsAbs in HIV-positive patients with lymphoma, preclinical studies exploring CAR T modifications that target HIV-specific antigens, and studies examining the interaction between ART and immunotherapies. If a study only focused on HIV-negative lymphoma populations, it was excluded unless there were comparative insights relevant to HIV-positive populations.

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting literature reviews. The PRISMA checklist is included as a Supplemental Material. A targeted search of the PubMed database was conducted to identify studies published between January 2000 and September 2024 related to the use of CAR T therapy and BsAbs in HIV-associated lymphoma. Search terms included combinations of “HIV,” “lymphoma,” “CAR T cell therapy,” “bispecific antibodies,” and “immunotherapy.” Articles were also identified through manual screening of reference lists from relevant publications.

All authors independently searched the literature and selected articles based on their relevance to the topic. Inclusion criteria comprised case reports, cohort studies, clinical trials, preclinical studies, and comprehensive reviews that addressed the efficacy, safety, or mechanistic basis of CAR T or BsAbs in PWH and lymphoma. Studies focusing exclusively on HIV-negative populations or unrelated malignancies were excluded.

A formal risk of bias assessment tool was not used. However, all included studies were critically appraised by the authors based on study design, sample size, and clarity of outcome reporting. Given the predominance of case reports and small observational studies, we interpreted findings with caution and considered potential sources of bias when synthesizing results.

Following title and abstract screening, a full-text review was performed on 67 articles. After applying inclusion and exclusion criteria, 54 studies were included in the final review. A PRISMA flow diagram summarizing the article selection process is included below. A PRISMA flow diagram summarizing the article selection process is presented in Table 1.

Table 1.

Simplified PRISMA flow diagram.

Stage	Number of records
Full-text articles assessed for eligibility	67
Full-text articles excluded	13
Studies included in qualitative synthesis	54

Results

CAR T in HIV patients with lymphoma: Specific mechanisms of CAR T therapy in HIV

CAR T therapy represents an innovative approach to treating cancer by modifying patients’ immune cells to identify and combat cancer cells. ¹⁰ These cells are engineered to express CARs that recognize specific antigens on cancer cells, such as CD19 and B-cell maturation antigen (BCMA). ¹⁰ Notably, CAR T therapy targets tumor cells independently of the presence of HLA molecules. ¹¹ When CAR T recognize cancer cells, and they initiate a cascade that triggers the release of pro-inflammatory cytokines, leading to the destruction of cancer cells. ¹¹ The evolution of CAR T therapy over time has aimed to enhance its effectiveness in treating cancer. ¹² Early CAR designs lacked sufficient costimulatory signals that are necessary for proper T-cell activation. ¹² Second-generation CARs addressed this limitation by incorporating the CD28 costimulatory signal, thereby enhancing their activation potential. Subsequent generations further refined CAR design by integrating multiple costimulatory signals and enabling CARs to release cytokines that activate the immune system. ¹²

CAR T therapy has revolutionized the treatment of various hematological malignancies, including acute lymphoblastic leukemia (ALL), multiple myeloma, and follicular lymphoma. ¹³ Clinical trials of anti-BCMA CAR T therapy have shown promising results, with complete remission (CR) rates reaching up to 85% in ALL and 100% in B-cell ALL (B-ALL) patients. ¹⁴ These outcomes underscore the efficacy and clinical significance of CAR T therapy in treating hematologic cancers.

Given its success in hematologic malignancies, there is interest in exploring CAR T therapy for other medical conditions, such as HIV. ¹⁵ Researchers hypothesize that CAR T could be engineered to recognize HIV antigens, potentially offering a new treatment strategy. ¹⁵ The HIV community is assessing CAR T therapy as a potential strategy for completely removing the HIV virus from its host. Given that CAR T treatment entails modifying the patient’s own T cells, the risk of graft-versus-host disease is avoided. This technique aims to elicit long-term immune memory to avoid viral rebound. ¹⁶

There are different approaches to the use of CAR T to treat HIV-infected cells. One approach involves modifying T cells to target HIV antigens using the CD4 receptor or neutralizing antibodies (NAbs) against HIV envelope glycoproteins like g120. ¹⁵ This poses a challenge due to the variability of the HIV envelope protein (qp120). This leads to limited efficacy of CAR T as they are designed to recognize specific epitopes of gp120, and the antigenic diversity among different strains limits their effectiveness. ¹⁶ Another strategy employs broadly NAbs (bNAbs) effective against various HIV strains. ¹⁵ These bNAbs attack highly conserved regions of the HIV envelope protein and have been demonstrated to be effective in vitro and in preclinical models. ¹⁶ By using bNAbs instead of CD4, CAR T can potentially avoid direct infection and maintain their cytotoxic activity against HIV-infected cells. ¹⁶

Bispecific T-cell engagers in HIV patients with lymphoma

Bispecific T-cell engagers (BiTEs) are a subtype of BsAbs, a category of antibodies containing two independent antigen-binding sites that allow for the linkage of two separate cells simultaneously. There are more than 100 established subtypes of BsAbs, ¹⁷ and they can be broadly categorized into three groups of binding characteristics: antibodies binding two separate tumor-associated antigens, antibodies binding a tumor-associated antigen and an immune cell antigen, and antibodies binding two separate immune cell antigens. ¹⁸ BiTEs fall into the second category, containing two single-chain variable fragments (scFvs) which are bridged by a flexible linker. ¹⁹ These scFvs characteristically co-target tumor cell antigens and T-cell CD3 subunits, stimulating T-cell activation and T-cell receptor crosslinking with resultant T-cell proliferation and cytokine release.^19,20

Ample research has investigated the therapeutic use of BiTEs in a wide variety of malignancies. Recent studies have shown promise in treating patients with multiple myeloma, B-cell non-Hodgkin lymphoma, and B-ALL due to impressive anti-tumor activity.^21,22 In solid tumors, BiTEs have yet to show clinically meaningful anti-tumor activity.^23,24 Thus far, research on the role of BiTEs has largely focused on patients with the aforementioned malignancies who are refractory to conventionally established therapies. ²²

Despite the ongoing research on BiTEs and BsAbs and their growing promise in the treatment of B-cell malignancies, minimal literature has explored the efficacy of these therapies on patients with HIV-associated lymphoma. Part of this gap is attributable to concerns about HIV-related adverse outcomes, such as viral reactivation and the possibility of HIV-associated symptoms convoluting the detection of novel agent-related adverse effects. While we were unable to identify any studies specifically studying the efficacy of BsAbs in patients with HIV-associated lymphomas, some studies on BsAbs have included patients with HIV. Trials involving agents such as Blinatumomab (NCT02003222, 15), Mosunetuzumab,^25,26 Epicoritamab (NCT03625037), and Glofitamab ²⁷ have allowed for the inclusion of patients with HIV, conditional on effective control of the virus.

In a setting where patients with HIV are less likely to receive treatment across a variety of malignancies (as compared with patients uninfected with HIV), ²⁸ HIV-associated malignancies remain a major cause of mortality among PWH.^29,30 Considering these hurdles for PWLH, studies exploring the efficacy of BsAbs and BiTEs in patients with HIV-associated lymphoma are warranted.

Clinical trials have demonstrated the efficacy of BiTEs in hematologic malignancies, though data in PWH remain limited. Blinatumomab, approved for relapsed/refractory B-ALL, achieved a 43% CR rate in Miminal Residual Disease (MRD)-positive patients, and up to 69% overall response rate (ORR) in some cohorts. ¹⁸ Its use in combination with dasatinib in Ph+ ALL further improved response rates, though outcomes in PWH were not reported. ³¹

Newer CD20 × CD3 BiTEs show promise in lymphomas. Mosunetuzumab combined with polatuzumab vedotin yielded a 72% ORR and 57% CR in relapsed/refractory Diffuse large B-cell lymphoma (DLBCL), ²⁵ while its use with lenalidomide in untreated follicular lymphoma demonstrated high response rates with manageable toxicity. ²⁶ Glofitamab showed a 58.1% ORR and 38.7% CR in real-world relapsed/refractory B-cell lymphoma, with mostly low-grade cytokine release syndrome (CRS). ²⁷

Although some of these trials allowed PWH with controlled viral loads, ²² none reported subgroup-specific outcomes. Earlier BiTEs, such as catumaxomab and solitomab, were limited by severe toxicities, including hepatotoxicity and gastrointestinal side effects, leading to early discontinuation.^23,24 These findings underscore the need for inclusive trial designs to clarify BiTE efficacy and safety in HIV-associated lymphomas.

Limitations of T-cell expansion in HIV

CAR T therapy has the potential to remarkably advance treatment in HIV-positive lymphoma patients. Current intensive protocols utilizing ART have a worse outcome compared to the HIV-negative lymphoma population. ³² In addition, current ART has not been able to eradicate latent reservoirs of HIV alone due to the integration of HIV DNA into the CD4 genome. ³³ Curing HIV could significantly reduce the risk of developing lymphoma in HIV-positive populations. However, implementing CAR T therapy for HIV patients with or without lymphoma highlights the need for modifications engineered specifically to address the challenges created by HIV. For example, patients with chronic HIV infections, who are more susceptible to developing lymphomas, tend to have low levels of HIV antigen expression in infected cells. ³⁴ Low antigen expression can result in ineffective CAR T expansion, as the CAR must interact with a specific antigen to trigger proliferation. Recent studies have begun to explore how to adapt the CAR design based on tumor type, burden, and antigen density. One study found that the specific use of 4-1-BB costimulatory domains in CD19 CARs resulted in the expression of an anti-exhaustion signal, following exposure to high tumor burdens. ³⁵ The 4-1-BB domain may be beneficial in treating high tumor burden or antigen density by reducing tonic signaling. ³⁶ Conversely, CD28 costimulatory domains in CD19 CARs are associated with a rapid onset of activity and faster exhaustion. ³⁶ The CD28 domain may be critical for malignancies with low antigen density, as it could help reach the T-cell activation threshold to be therapeutic. It is important to acknowledge that more research needs to be conducted to generalize these results to future cases. Additional complexities associated with treating HIV-positive lymphoma patients with CAR T therapy include the possibility of viral reactivation, depressed immune cell function, and the interactions between antiretroviral drugs and immunotherapeutic agents. As research advances, future clinical trials need to thoroughly investigate these intricacies to determine effective CAR T therapy. CAR T optimization for HIV-positive lymphoma patients will continue to improve as novel markers are discovered to ultimately 1 day find a cure.

Clinical data

Clinical trials and data relating to CAR T therapy for lymphoma in patients who are HIV positive are particularly scant. Furthermore, data relating to BsAbs in this subset of patients is notably absent in the literature. The gap in data is most likely due to the fact that patients with HIV are not included in clinical trials. Most of the data we have is contained within case reports.

A study identified nine cases where CD19-targeted CAR T therapy was used in patients with lymphoma and HIV. ³⁷ Six cases were determined to have sufficient data and were used in the analysis.^38–41 All of these patients had diffuse large B-cell lymphoma. The mean CD4 count for these patients was 221 cells/μL, ranging from 52 to 629. Four of the six patients in the review had an undetectable viral load. One of the patient’s viral loads was not specified. Four of the six patients responded to the therapy, and three of these patients achieved CR. One of the patients was refractory after 15 days of the treatment, and another patient showed disease progression despite treatment. Four of these six patients had low-grade CRS and higher-grade immune effector cell-associated neurotoxicity syndrome (ICANS). The reported follow-up time in these patients was limited.^37–41

In an additional case report, a 66-year-old woman with diffuse large B-cell lymphoma, HIV, and end-stage renal disease was treated with axicabtagene and ciloleucel. This patient had grade 1 CRS and grade 2 ICANS. This patient received a complete response to therapy. ⁴²

Due to the promise that CAR T therapy has shown in treating lymphoma in patients living with HIV, other studies are currently being developed to assess the efficacy and safety in this patient population. ⁴³

CAR T therapy and HIV amplification

Since CAR T therapy involves modification of T cells and HIV infects T cells, there are various theoretical concerns regarding the feasibility of CAR T therapy in HIV-infected patients. During the production process of CAR T, the T cells are collected from the patients themselves, and during ex vivo culture and expansion of T cells, there is reasonable concern that the virus could replicate and lead to a higher viral load upon reinfusion. ¹⁵ There is evidence of clonal expansion of infected resting memory CD+ T cells both in HIV patients under CAR T therapy and in ex vivo culture systems. ¹⁵ To mitigate this potential risk, co-culturing HIV-positive T-cell lines in the presence of ART could be undertaken. It has been shown that such co-culturing leads to the killing of HIV-infected cells in ex vivo cultures. ¹⁵ This step in the manufacturing process may ensure that the expansion phase does not amplify the virus, keeping the viral load low or undetectable even after reinfusion.

In addition, since CAR T are modified T cells, they could potentially get infected in/ex vivo and serve as a vector for viral spread. However, there are in vitro studies that have used gene editing techniques to eliminate CCR5 expression to create HIV-resistant CAR T. ³⁷ Another possible mechanism of HIV amplification may be CAR T-associated CRS, which could theoretically activate latent HIV reservoirs. ¹⁶

These theoretical risks have historically led to the exclusion of HIV patients from pivotal trials investigating the use of CAR T in lymphoma therapy. Gene editing techniques to create HIV-resistant CAR T, the use of ART during the manufacturing process, and continuation of ART in the patient may help address these risks. It is also important to address that although there are theoretical risks, recent clinical evidence is pointing toward the safe and effective nature of such therapy in HIV-positive patients. ⁴⁴ A study involving six HIV-positive lymphoma patients undergoing CAR T therapy suggests viral load can be well-controlled with ART.

HIV and lymphodepletion

The advent of CAR T therapy and BsAbs has been promising in the treatment of lymphoma. However, lymphodepletion in HIV patients presents significant immunological challenges, which necessitate an assessment regarding the feasibility of such therapy in HIV-infected lymphoma patients. The preexisting immune dysfunction in HIV patients makes it necessary to implement strategies to balance lymphodepletion therapy with immune preservation. ¹⁶ Studies have shown that CAR T therapy should be considered in such patients, but with special considerations. Prolonged lymphopenia following post-CAR T therapy has been shown to increase susceptibility to opportunistic infections, making antimicrobial prophylactic therapy important in these patients. ⁴⁵ In addition, CAR T function is not impaired in patients with HIV, and such therapy can be administered with comparable safety and efficacy, at least in those patients with viral remission achieved on ART. ³⁷ Since lymphodepletion therapy is not required with regard to BsAbs, these logistical hurdles arising specifically due to lymphodepletion therapy can be avoided. BsAbs could also engage natural killer cells to target HIV-infected cells, potentially offering therapeutic benefits. ⁴⁶

Discussion

According to the literature, CAR T therapy represents a novel and transformative approach to treating HIV-associated lymphoma and HIV itself. In the context of lymphoma, CAR T therapy has shown great efficacy in relapsed and refractory cases, with clinical evidence suggesting that HIV-positive patients can achieve comparable results when treated with this approach.

HIV viral load plays an important role in lymphoma development. High viral loads are associated with chronic immune activation, which may contribute to lymphoma risk. ART reduces viral load and is known to decrease the incidence of HIV-associated malignancies. Most immunotherapy trials currently exclude patients with uncontrolled HIV due to safety concerns, which limits data on this higher-risk population.

Different studies have provided valuable insight into the real-world applications of CAR T therapy in PWH. A study from the AIDS Malignancy Consortium (AMC) and the Center for International Blood and Marrow Transplant Research (CIBMTR) demonstrated that CD19-directed CAR therapy has shown promise in treating relapsed or refractory B-cell lymphomas in PWH. ⁴⁷ This study represents the largest cohort of PWH treated with CAR T, providing comparable safety and efficacy outcomes to those seen in HIV-negative populations. Some patients experienced self-limited CRS and neurotoxicity, which was consistent with previous CAR T studies. Encouraging survival rates at 3 and 6 months further support CAR T as a viable option for treating relapsed or refractory B-cell lymphomas in patients with HIV. ⁴⁷ Another study also reported the treatment of chemotherapy-refractory, high-grade B-cell lymphoma in two HIV-positive patients. ⁴⁰ Despite concerns regarding the safety of manufacturing CAR T from HIV-infected T cells, both patients received anti-CD19 CAR T and achieved durable remission. The study highlights that CAR T therapy can be safely administered alongside ART and demonstrates its potential efficacy in this patient population. ⁴⁰ Another review article of case reports synthesized the literature on the use of CAR T therapy in PWH, and it discussed the feasibility, safety, and efficacy of the approach. ⁴⁸ A key case report discussed in the article describes the treatment of ten individuals with HIV and non-small-cell lung carcinoma using nivolumab, which showed comparable response rates and safety outcomes to non-HIV-infected patients. The study also reported no severe adverse reactions from the treatment. ⁴⁸ These findings highlight the potential for CAR T therapy in cancer treatment.

In reviewing the available literature (Table 2), several case reports and small series suggest that CAR T therapy is feasible and potentially effective in PWH who have lymphoma. Across six reported cases, a majority achieved clinical responses, including CR. Trials such as AMC/CIBMTR support comparable safety and efficacy to HIV-negative populations. In contrast, BsAb trials such as those involving Blinatumomab, Mosunetuzumab, and Glofitamab report high response rates in relapsed hematologic malignancies, but have limited inclusion of PWH and no subgroup-specific efficacy data. This disparity underscores the need for more inclusive trial designs and reporting standards to better understand outcomes in immunocompromised populations.

Table 2.

Summary of clinical studies involving CAR T therapy and bispecific antibodies in lymphoma patients with or without HIV.

Study/trial	Agent	Population	PWH included?	Key results
Hattenhauer et al. 37	CD19 CAR T	Six HIV+ DLBCL patients	Yes	4/6 responded; three CRs; mild CRS/ICANS
AMC/CIBMTR Study 47	CD19 CAR T	Largest cohort of PWH with lymphoma	Yes	Comparable safety and efficacy to HIV-negative patients
Yuen et al. 41	Axicabtagene Ciloleucel	One HIV+ DLBCL patient	Yes	Complete response; grade 1 CRS and grade 2 neurotoxicity
Abramson et al. 40	CD19 CAR T	Two HIV+ high-grade lymphoma patients	Yes	Both achieved durable remission
Mosunetuzumab + Polatuzumab 25	BiTE + Antibody-drug conjugate (ADC)	Relapsed/refractory DLBCL	Yes (some)	72% ORR, 57% CR
Glofitamab 27	BiTE	Real-world R/R B-cell lymphoma	Yes (some)	58.1% ORR, 38.7% CR

Note. “PWH included” refers to PWH who were allowed in the trial, typically with controlled viral load on ART, unless otherwise specified.

AMC: AIDS Malignancy Consortium; ART: antiretroviral therapy; BiTEs: bispecific T-cell engagers; CIBMTR: Center for International Blood and Marrow Transplant Research; CR: complete response; CRS: cytokine release syndrome; HIV: human immunodeficiency virus; ICANS: immune effector cell-associated neurotoxicity syndrome; ORR: overall response rate; PWH: people with human immunodeficiency virus.

Many of the included studies had inherent methodological limitations. The case reports and small cohort studies frequently lacked control groups, had limited follow-up periods, and often provided incomplete outcome data. These limitations were acknowledged and considered in the synthesis and interpretation of the findings.

Despite its promise, the feasibility of CAR T therapy in patients with HIV needs further exploration due to the unique challenges this population faces. The immunosuppressive nature of HIV may impact CAR T expansion and persistence, potentially limiting therapeutic effects. In addition, as previously discussed, CRS or viral reactivation during CAR cell expansion must be carefully addressed. These case reports have provided encouraging preliminary data. Nonetheless, larger clinical trials are needed to establish the safety and the long-term benefits of CAR T therapy in patients with HIV. To ensure safety and treatment efficacy in this vulnerable population, careful patient selection, optimized CAR T-cell engineering, and continued CAR T throughout treatment are crucial.

This review is subject to several limitations. Most of the available data are derived from case reports and small observational studies, limiting external validity. The exclusion of PWH from clinical trials has contributed to a paucity of high-quality evidence, particularly randomized controlled trials. In clinical practice, patients with newly diagnosed HIV and lymphoma may present with high viral loads, making them ineligible for clinical trials that require viral suppression. One way to improve representation is to allow flexible inclusion criteria where patients can start ART promptly, achieve some viral control, and then be re-evaluated for trial eligibility. Dedicated sub-studies or registry-based data collection could also help capture outcomes in these patients who are typically excluded. In addition, patient heterogeneity, such as variations in CD4 counts, ART regimens, and lymphoma subtypes, complicates direct comparisons and standardized conclusions. Many of the mechanistic insights discussed are based on preclinical or ex vivo models and may not fully translate to clinical outcomes. Theoretical risks, such as viral amplification during manufacturing, CAR T susceptibility to HIV infection, and immunosuppressive complications, are not yet fully quantified in large-scale studies. Lastly, the scope of this review was limited to studies indexed in PubMed, potentially omitting relevant data from other sources or non-English literature.

Conclusion

CAR T therapy and BsAbs represent promising approaches for the treatment of HIV-associated lymphoma. Preliminary data from case reports suggest that CAR T therapy may be safe and effective in PWH, with outcomes comparable to HIV-negative populations and manageable side effects such as low-grade CRS and neurotoxicity. However, most of the available evidence is limited to small series or case reports, and BsAb data in this population remain scarce due to trial exclusions. Larger, prospective clinical trials are urgently needed to establish efficacy, optimize treatment strategies, and ensure that PWH are adequately represented in immunotherapy research. Until such data become available, these therapies should be considered investigational and best evaluated within the context of clinical trials.