Received: 15 January 2023 Accepted: 9 May 2023

DOI: 10.1111/hiv.13514

REVIEW ARTICLE

Enabling CAR T-cell therapies for HIV-positive lymphoma

patients – A call for action

Sandra Tessa Hattenhauer 1 | Rebekka Mispelbaum 1 | Marcus Hentrich 2 |

Christoph Boesecke 3,4 | Malte Benedikt Monin 3,4

1
Department of Oncology, Hematology,
Rheumatology and Immune-Oncology, Abstract
University Hospital Bonn, Bonn, People living with HIV have a higher risk of developing lymphoma. Outcomes
Germany
for people living with HIV with relapsed or refractory (r/r) lymphoma remain
2
Department of Internal Medicine III, Red
poor. For this group of patients, chimeric antigen receptor (CAR) T-cell ther-
Cross Hospital Munich, Munich,
Germany apy represents a new successful treatment strategy. However, people living
3
Department of Internal Medicine I, with HIV were not included in pivotal trials, so data are limited to case reports.
University Hospital Bonn, Bonn, We searched the PubMed and Ovid technologies databases for literature until
Germany
4
1 November 2022 using the terms ‘HIV and CAR-T’, ‘HIV and lymphoma’
German Centre for Infection Research
(DZIF), partner-site Cologne-Bonn, Bonn, and ‘HIV and CAR-T and lymphoma’. Six cases with sufficient information
Germany were included in the review. The mean CD4+ T-cell count before CAR T-cell
therapy was 221 cells/μL (range 52–629). The viral load was below the limit
Correspondence
Malte Benedikt Monin, Department of of detection in four patients. All patients had diffuse large B-cell lymphoma
Internal Medicine I, Venusberg-Campus (DLBCL) and were treated with gamma-retroviral-based axicabtagene cilo-
1, 53127 Bonn, Germany.
Email: malte_benedikt.monin@
leucel. Four patients developed cytokine-release syndrome (CRS) grade 2 or
ukbonn.de less or immune effector-cell-associated neurotoxicity syndrome (ICANs)
grade 3–4. Four of six patients responded to CAR T-cell therapy (three com-
plete remissions, one partial remission). In summary, there are no clinical
reasons to restrict the use of CAR T-cell therapy in people living with HIV
with r/r DLBCL. According to the current data, CAR T-cell therapy was safe
and effective. In people who meet the standard criteria for CAR T-cell ther-
apy, this treatment approach could significantly improve the unmet need for
more effective treatment options for people living with HIV with r/r
lymphoma.

KEYWORDS
CAR T-cell therapy, CAR T-cells, DLBCL, HIV, lymphoma

INTRODUCTION

Sandra Tessa Hattenhauer and Rebekka Mispelbaum contributed The probability of developing both non-Hodgkin lympho-
equally to this work and share first authorship. mas (NHLs) and/or Hodgkin lymphomas (HLs) is

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.

HIV Med. 2023;1–8. wileyonlinelibrary.com/journal/hiv 1

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2 HATTENHAUER ET AL.

markedly raised in people living with HIV with low remain the most common cause of AIDS-related deaths
CD4+ T-cell counts. Furthermore, prolonged HIV virae- in the Western world, and the outcomes of people living
mia is a risk factor for developing NHLs [1–3]. Even with HIV with r/r lymphoma remain poor [19,20]. For
when receiving successful combined antiretroviral ther- this patient group, chimeric antigen receptor (CAR) T-
apy (ART), people living with HIV have an increased risk cell therapy represents a new successful treatment strat-
for occurrence of lymphomas [1]. Given the wide use of egy in the r/r setting.
combined ART and the subsequent improved life expec- CAR T-cells are ex vivo genetically engineered T-cells
tancy of people living with HIV, age-related lymphoid with a CAR, targeting a defined surface antigen on malig-
neoplasms are expected to be more frequently diagnosed nant cells (e.g. CD19 predominantly for B-NHLs or B-cell
in people living with HIV in the future [4]. maturation antigen [BCMA] for multiple myeloma) [21].
The 2017 World Health Organization classification of To manufacture CAR T-cells, patients undergo leuka-
tumours of haematopoietic and lymphoid tissues distin- pheresis to collect leukocytes from peripheral blood. The
guishes three groups of lymphomas associated with HIV patient's isolated T-cells are modified by viral transduc-
infection: lymphomas also occurring in immunocompe- tion to express the CAR for the desired target cells. Either
tent patients; those more specifically related to HIV, gamma-retroviral or lentiviral vectors are used to transfer
such as primary effusion lymphoma or plasmablastic this new genetic material into the T-cell. CAR T-cells are
lymphoma; and lymphomas occurring in other immuno- then expanded, activated, and reinfused into the patient
deficiency states [5]. after lymphodepleting chemotherapy to induce a specific
The oncological treatment standards in people living and direct cytotoxic tumour attack (Figure 1) [22,23].
with HIV should not differ from those in lymphoma This new treatment approach has resulted in high
patients without HIV. Of note, combined ART is an response rates and prolonged survival rates in heavily
important, additional part of lymphoma treatment in pre-treated patients with lymphomas. For example, axi-
people living with HIV to suppress viral replication and cabtagene ciloleucel, as second-line therapy for DLBCL,
restore immune function [6]. In lymphoma patients with resulted in significant improvement in event-free survival
HIV receiving effective combined ART, both complete and response rates compared with standard of care [24].
remission (CR) and survival rates were significantly The European Medicines Agency has approved CAR T-
improved [7]. Today, the outcomes of people living with cell therapy for a growing number of r/r malignant B-cell
HIV with lymphomas is therefore mainly determined by lymphomas, including DLBCL, follicular lymphoma,
lymphoma-related factors such as lymphoma subtype mantle cell lymphoma, and multiple myeloma. However,
and the international prognostic index, and the impact patients with HIV and lymphoma were not represented
of HIV-related factors has substantially declined [8–10]. in licensing trials for CAR T-cell therapy, which impedes
Accordingly, the cancer-related mortality of some specific the use of this novel treatment approach in people living
lymphoma subtypes, such as diffuse large B-cell with HIV [25–30].
lymphoma (DLBCL) and HLs does not differ from that in The aim of this review is to summarize the currently
patients without HIV [11]. With respect to the most com- limited published data on CAR T-cell therapy in patients
mon AIDS-related lymphoma (ARL) subtypes (DLBCL with HIV and lymphoma, to discuss unresolved prob-
and Burkitt lymphoma) 2-year overall survival rates were lems, and to argue for the inclusion of people living with
reported to be in the range of 70%–75% [12,13]. In the HIV with lymphoma in cohorts and trials of CAR T-cell
German HIV-lymphoma cohort study, 64% of patients therapy. We reviewed the available literature until
with ARL experienced CR with first-line chemotherapy, 1 November 2022. All cases were identified via a search
11.4% of whom relapsed [14]. for indexed articles in the PubMed and Ovid technologies
Similar to lymphomas in patients without HIV, the databases using the terms ‘HIV and CAR-T’, ‘HIV and
treatment approach for patients with relapsed or refrac- lymphoma’ and ‘HIV and CAR-T and lymphoma’. We
tory (r/r) lymphoma responding to salvage chemotherapy also included the most recent data, which were presented
is autologous stem cell transplantation (ASCT) following at the 64th annual meeting of the American Society of
high-dose chemotherapy. Several studies found no signif- Hematology in 2022.
icant differences in the outcomes of patients with ARL
undergoing ASCT compared with controls without HIV
[15,16]. Allogenic stem cell transplantation has also been R E S U LTS OF TH E L IT E R A T U R E
successfully performed in patients with HIV with refrac- REVIEW
tory lymphoma [17,18].
Despite the markedly improved overall outcomes in Nine published case reports on CD19-targeted CAR T-cell
patients with HIV and lymphoma, B-cell lymphomas therapy in patients with lymphoma and HIV were
 14681293, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13514 by Nat Prov Indonesia, Wiley Online Library on [29/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HIV MEDICINE 3

F I G U R E 1 CAR T-cell therapy. After T-cell apheresis, viral transfer of the CAR-encoding gene is conducted to express a specific CAR
on the surface of the T-cells. CAR T-cells are reinfused into the patient and induce a cytotoxic attack, resulting in lymphoma cell death [22].
CAR, chimeric antigen receptor. Adapted from Almåsbak et al. [22], figure created with BioRender.com.

identified [31–36]. Three cases were excluded from the progression of the central nervous system with a systemic
analysis because data were insufficient (Table 1) [34,35]. CR at first staging after 4 months. The reported follow-up
We found no reports on the use of BCMA-targeted CAR data were limited, and the observation period after therapy
T-cells for the treatment of patients with HIV and multi- start was only 4 months or less, except for one case.
ple myeloma. The average age of the patients was
54 years (range 47–66). The sex distribution was 20%
women and 80% men. The mean CD4+ T-cell count was Emerging data
221 cells/μL (range 52–629). Viral load was below the
limit of detection in four patients, was 67/mL in one The interim analysis of a prospectively collected registry
patient, and was not documented in one patient. All study of anti-CD19 CAR T-cell therapy for patients with
patients had DLBCL, and most patients received CAR HIV and B-cell lymphoma was presented at the 64th
T-cell therapy as fourth-line therapy. If documented, annual meeting of the American Society of Hematology
lymphocyte depletion was performed with fludarabine 2022. Data from 21 patients with HIV treated with axi-
and cyclophosphamide. All patients were treated with cabtagene ciloleucel or brexucabtagene autoleucel
gamma-retroviral-based axicabtagene ciloleucel. Four were described. The median CD4 count before CAR T-
patients experienced cytokine-releasing syndrome cell therapy was 228 cells/mm3, and the median HIV
(CRS) of grade 2 or less and immune effector-cell- viral load, if reported, was 21 copies/mL. CRS occurred
associated neurotoxicity syndrome (ICANS) of grade in 69%, and ICANS occurred in 23% of patients. All
3–4, and one patient showed no side effects. Four of six cases of CRS and ICANS resolved. The overall survival
patients responded to CAR T-cell therapy (three CR, at 6 months was 64%, which the authors deemed com-
one partial remission). One patient was primarily refrac- parable to that in patients without HIV. The study is
tory after 15 days, and one patient showed isolated disease ongoing [37].
 4

TABLE 1 Use of CAR T-cell therapy in patients with HIV (n = 6).

Age Combined CD4+ T-cells T-cells Viral load Side effects (grade)/ Response
Case References (years) Sex ART (cells/μL) (cells/μL) (copies/mL) Lymphoma CAR product therapy (follow up)
1 [33] 47 m Yes 52 n.s. 67 DLBCL Axicabtagene CRS (grade 2)/ CR (1 year)
ciloleucel tocilizumab, steroid
ICANS (grade 3)/
steroid
2 [33] n.s. m Bictegravir/ 127 n.s. Undetectable DLBCL Axicabtagene no CRS CR (at least 28 days)
emtricitabine/ ciloleucel no ICANS
tenofovir
alafenamide
3 [31] n.s. n.s. n.s. 127 n.s. Undetectable DLBCL Axicabtagene n.s. CR (n.s.)
ciloleucel
4 [32] 49 m Yes 170 847 Undetectable DLBCL Axicabtagene CRS (grade 1)/steroid PR (PD after
ciloleucel ICANS (grade 2)/ 2 months)
steroid
5 [36] 66 f n.s. 629 n.s. Undetectable DLBCL Axicabtagene CRS (grade 1)/steroid PD (isolated CNS
ciloleucel ICANS (grade 2)/ recurrence after
steroid 4 months with
systemic CR)
6 [34] 53 m Yes n.s. n.s. n.s. DLBCL Axicabtagene CRS (grade 1)/ PD (after 15 days)
ciloleucel anakinra, steroid
ICANS (grade 3)/
anakinra, steroid

Abbreviations: ART, antiretroviral therapy; CAR, chimeric antigen receptor; CNS, central nervous system; CR, complete response; CRS, cytokine releasing syndrome; DLBCL, diffuse large B-cell lymphoma; f, female;
ICANS, immune effector cell-associated neurotoxicity syndrome; m, male; n.s., not stated; PD, progressive disease (including recurrent disease); PR, partial response.
HATTENHAUER ET AL.

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HIV MEDICINE 5

Controversial issues Low-level viraemia and blips

According to the included case reports, the use of the Under effective combined ART, the viral load in people
anti-CD19 CAR T-cell product axicabtagene ciloleucel in living with HIV is rapidly suppressed and is undetectable
people living with HIV with DLBCL is promising, as it in almost all patients. However, some individuals have
showed therapy responses in short-term follow-up and residual low-level viraemia (i.e., a viral load between
an acceptable toxicity profile. However, given the limits, 50 and 200 copies/mL), which is not linked to treatment
potential concerns regarding CAR T-cell therapy in the failure as long as the viral load is <200 copies/mL [43–
treatment of patients with HIV and lymphoma must be 45]. Moreover, 20%–40% of people living with HIV under
considered, at least theoretically. combined ART experience transient, small increases in
viral load (i.e., <200 copies/mL), so-called ‘blips’ [46].
The cause of blips is multifactorial, but sporadic viral
T-cell status shedding from latent reservoirs seems to be an important
aspect. Both acute concomitant infections and vaccina-
One of the main difficulties in the manufacturing process tions have been described as favouring blips, probably by
is to achieve the target dose of CAR T-cells [38]. A suffi- elevating the level of chronically infected cells and
cient number of apheresed CD4+ T-cells is a critical thereby replenishing the viral reservoirs [47–49]. In
aspect for successful CAR T-cell production and for CAR patients with cancer, especially when receiving chemo-
T-cell function, and presumably for long-term effects therapy, blips must be expected. The occurrence of both
[39,40]. It is recommended that therapies that may conditions, low-level viraemia and/or blips, is considered
reduce T-cell counts, such as bendamustine, are avoided a controlled HIV infection and is not a reason to exclude
before apheresis [41]. Lower CD4+ T-cell counts in peo- people living with HIV from CAR T-cell therapy. Of note,
ple living with HIV might therefore be problematic for in one case, CAR T-cell therapy was successful in a
CAR T-cell generation and efficacy. In particular, people patient with a viral load of 67/mL [33].
who present with late-stage HIV with poor CD4 cell
count at time of diagnosis more frequently fail to recover
to normal CD4 cell counts [42]. However, these case Lentiviral vectors
reports indicate that the manufacturing of CAR T-cells
for patients with controlled HIV disease and lower CD4+ As HIV belongs to the lentiviral genus, patients with lym-
T-cell count seems feasible. In one case, CAR T-cells were phoma without HIV may have false-positive results after
successfully generated for a patient with HIV and lym- lentiviral-based CAR T-cell therapy [50]. Additionally,
phoma with 52 cells/mm3 CD4+ T cells at the time of the use of lentiviral vectors during the manufacturing
apheresis [31]. We found no published reports on unsuc- process of CAR T-cells bears the theoretical risk of an
cessful CAR T-cell generation in people living with HIV. uncontrolled increase of CARs in patients with HIV dur-
The optimal CD4+/CD8+ CAR T-cell ratio has not been ing replication of the human immunodeficiency virus
clarified, and the ratio differs according to the specific in vivo. This must particularly be discussed in patients
CAR T-cell product [23]. Notably, in all published cases with low-level viraemia and/or blips. To the best of our
of CAR T-cell treatment for r/r HIV–lymphomas, axicab- knowledge, there are no case reports of the use of
tagene ciloleucel was used, a CAR T-cell product without lentiviral-based CAR T-cell therapy in patients with HIV
a specific CD4+/CD8+ ratio [26,31–36]. with lymphoma so far, probably due to these concerns.
Therefore, only gamma-retroviral-based CAR T-cells can
be recommended in patients with HIV and lymphoma
Infectiousness for the time being.

There might be concerns about the risk of HIV transmis-

sion for manufacturing staff during production of CAR T- Interactions
cells for patients with HIV. However, the transmission
risk is negligible under successful combined ART and is Current combined ART is mainly based on integrase
significantly reduced with high hygiene standards for inhibitors (particularly in people living with HIV undergo-
CAR T-cell production. The blood of people living with ing cancer treatment), so the potential for drug–drug inter-
HIV is routinely processed for diagnostic and ASC prod- actions between combined ART and chemotherapy is low
uct manufacturing [15]. This must also be applied to the [51]. No interactions between ART and fludarabine/cyclo-
CAR T-cell manufacturing process. phosphamide (standard lymphodepleting chemotherapy)
 14681293, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hiv.13514 by Nat Prov Indonesia, Wiley Online Library on [29/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 HATTENHAUER ET AL.

have been described by the interaction checker of the Uni- T-cell therapy – preferably in the setting of clinical
versity of Liverpool or in the presented case reports trials. The authors believe there are no theoretical con-
[52,53]. Also, with regard to the pharmacology of CAR-T cerns about the use of BCMA-targeted CAR T-cells in
cells, an interaction with or direct influence of combined the treatment of patients with HIV and multiple mye-
ART on CAR-T cells is not expected. The reported CR rate loma. However, the use of lentiviral-based CAR T-cells
in the case series gives no indication of a reduced thera- in people living with HIV cannot be recommended for
peutic effect of CAR T-cell treatment. the time being. In conclusion, CAR T-cell therapy could
significantly address the unmet need for more effective
treatment options for people living with HIV with r/r
Side effects lymphoma.

The most relevant side effect of CAR T-cell therapy is AUTHOR CONTRIBUTIONS
CRS. The clinical symptoms of CRS range from fever and Sandra Tessa Hattenhauer, Rebekka Mispelbaum, and
nausea to life-threatening capillary leakage with hypoxia Malte B. Monin: analysis and interpretation of the litera-
and hypotension. Interleukin (IL)-6, a proinflammatory ture; drafting of the manuscript. Marcus Hentrich, Chris-
cytokine, is assumed to induce a proinflammatory signal- toph Boesecke: critical revision of the manuscript for
ling pathway, which leads to CRS. The exact pathome- important intellectual content.
chanism of IL-6 is not completely understood, but CRS
responds to treatment with the IL-6 receptor blocker toci- C O N F L I C T O F I N T E R E S T S T A TE M E N T
lizumab, supporting the relevance of this cytokine for M.B.M. has received travel expenses and honoraria
CRS [54,55]. Elevated IL-6 levels have been observed in from Gilead, Pfizer, and Virology Education. S.T.H. has
people living with HIV [56]. Since higher IL-6 levels have received travel expenses from Janssen and Takeda.
been shown to predict CRS, the higher cytokine levels of R.M. has received travel expenses from Gilead and
people living with HIV might be associated with an Takeda. MH has received honoraria for lectures and/or
increased risk for CRS. The available case reports do not consultancies from Amgen, Astra Zeneca, EusaPharma,
show a higher rate or grade of CRS in this patient group. Celgene, Janssen, Jazz Pharma, Sanofi, and Takeda. CB
However, low or undetectable viral loads are associated has received honoraria for lectures and/or consultancies
with lower IL-6 levels, a group the case reports are lim- from AbbVie, Gilead, Janssen, MSD, and ViiV. Academic
ited to [56]. For a final evaluation of side effects of CAR funding was received from DFG, Deutsche Leberstiftung,
T-cell treatment in people living with HIV, more data are DZIF, Hector Stiftung, NEAT ID. However, these activi-
urgently needed. ties have no potential conflicts of interest with the
manuscript.

C O N C L U S IO N ACKNOWLEDGEMENT
Open Access funding enabled and organized by Pro-
Since people living with HIV were not included in the jekt DEAL.
pivotal trials, available data to date are limited to case
reports [25–30]. New standards for the inclusion of peo- DA TA AVAI LA BI LI TY S T ATE ME NT
ple living with HIV in oncological clinical trials have gen- Data sharing not applicable to this article as no datasets
erally been demanded by the American Society of were generated or analysed during the current study.
Clinical Oncology [57]. The goal is to offer the same ther-
apeutic standards of lymphoma therapy for people with
ORCID
and without HIV, considering combined ART as a con-
Malte Benedikt Monin https://orcid.org/0000-0002-
comitant medication [31]. Fortunately, a phase I study of
8794-3612
CAR T-cell therapy in people living with HIV is being
conducted (NCT05077527) [58].
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