‘A true travesty’: Despite new data and guidance, people with HIV still lack access to CAR-T

Individuals living with HIV historically have been at higher risk for non-Hodgkin lymphoma.

They also are considerably more likely to die of the disease than individuals without HIV, according to an NCI-led study (adjusted HR = 7.23; 95% CI, 1.7-2.3).

The proliferation of antiretroviral therapies and more effective cancer treatments has reduced the proportion of those who die of HIV-related malignancies. Nevertheless, non-Hodgkin lymphoma remains the leading cause of cancer-attributable deaths (3.5%) among those living with HIV, according to another NCI analysis.

Many of these individuals develop treatment-resistant disease that requires more than traditional chemoimmunotherapies.

Chimeric antigen receptor T cells are a significant advance in the treatment of high-risk and advanced non-Hodgkin lymphoma; however, to date, no person living with HIV has been eligible for treatment with investigational CAR-T via clinical trials. Other patients have been denied access to the therapy due to lack of insurance coverage or manufacturer’s prohibition because of HIV infection.

“There is still a perception that people living with HIV are more susceptible to infectious complications and, therefore, should not even be assessed for certain, more intensive [cancer] therapies,” Stefan K. Barta, MD, associate professor of clinical medicine at Perelman School of Medicine at University of Pennsylvania and director of the T-cell lymphoma program at Abramson Cancer Center, told Healio | Cell Therapy Next. “A disproportionate [number] of people living with HIV come from underrepresented minority groups, so there clearly is also an access-to-care issue.”

Healio | Cell Therapy Next spoke with several clinicians about new data that suggest CAR-T is equally effective for individuals with HIV as those without, the barriers that traditionally prevented individuals with HIV from accessing CAR-T, and the steps that can be taken to expand access to the modality in both clinical trials and real-world practice.

Preliminary data

Research to confirm CAR-T’s safety and effectiveness for immunocompromised patients is essential before access to the modality can be expanded for people living with HIV.

However, because these individuals have been prohibited from registrational trials, data in this area are scarce.

Results of a small retrospective study presented at last year’s ASH Annual Meeting and Exposition suggested — for the first time — that CAR T-cell therapy is equally effective for people with HIV and conferred no additional safety risks.

The study — conducted by members of the AIDS Malignancy Consortium (AMC) and the Center for International Blood and Marrow Transplant Research (CIBMTR) — included 27 patients (median age, 55 years; range, 29-70; 81% men; 52% white; 30% Black; 11% Latino) with HIV who received CD19-directed CAR T-cell therapy for B-cell lymphoid malignancies.

The analysis included 19 evaluable patients.

Ten patients (53%) achieved objective response to CD19-directed CAR-T, including eight (42%) who achieved complete response.

Fourteen patients (74%) developed cytokine release syndrome, but researchers reported no cases of grade 3 or grade 4 CRS. Five patients (26%) developed immune effector cell-associated neurotoxicity syndrome, including three with grade 3 symptoms and one with grade 4 symptoms.

“The outcomes — based on [these] preliminary data — appear to be equivalent to that reported [among] patients without HIV,” Barta said.

Barta called the results reassuring but cautioned they must be confirmed prospectively, such as an AMC-sponsored study that is in the final planning stages.

‘A different animal’

The exclusion of people living with HIV from clinical trials for novel cancer therapies has been a long-standing problem, particularly in the immunotherapy age, Barta said.

Four FDA-approved products treat some form of large B-cell non-Hodgkin lymphoma. None of the registrational trials that led to approval included individuals with HIV.

Most trials automatically disqualify those with active HIV infection regardless of other parameters, Barta said.

“This is an issue that needs greater attention from regulatory authorities and those who conduct these clinical trials,” he said.

Even trial criteria designed to be more inclusive often rely on CD4 counts, which may not be the most reliable measure given that many people who receive CAR-T in clinical trials have low CD4 counts due to depletion from prior cancer therapies.

Clinical trial access in large B-cell lymphoma is particularly important considering about one-quarter of patients — regardless of HIV status — are not cured by first-line treatment.

The additional variable of a particularly high-risk population means increased access to CAR-T for those living with HIV cannot be minimized, according to Ariela Noy, MD, an attending physician at Memorial Sloan Kettering Cancer Center who specializes in the treatment of HIV/AIDS-related lymphoma.

“People with HIV are discriminated against wholesale by investigators, both on the academic side and by pharma — unequivocally,” Noy told Healio | Cell Therapy Next. “It is a travesty for those patients that they have been excluded for historic reasons that are no longer valid.”

Physician bias can play a role, and industry sponsors may refrain from including those with HIV in their trial designs either due to stigma or an attempt to protect the integrity of their study results, Noy added.

There is no reason why individuals living with HIV should be prohibited from participating in cancer clinical trials provided they are under physician supervision and their disease is well controlled, according to Paul A. Volberding, MD, professor emeritus of medicine at University of California, San Francisco, and chief medical editor of Healio | Infectious Disease News.

Volberding — a cancer specialist by training — worked on early trials that evaluated antiretroviral therapy in HIV infection and later became co-director of UCSF’s Center for AIDS Research.

Because HIV is a disease of the immune system, Volberding said he understands the anxiety that sponsors and investigators may have including individuals living with the virus in registrational trials of immune-based cancer therapies.

“HIV is currently a different animal than it was in its early days, and those days are gone,” Volberding told Healio | Cell Therapy Next.

As investigators gain experience with later-stage trials of novel cell therapies, it would be to their benefit to treat a more inclusive clinical trial population that more accurately reflects real-world practice, he added.

“HIV is now so treatable that people living with the disease can live essentially normal lifespans,” Volberding said. “Because immunotherapies have become so important in treating malignancies — especially lymphomas — I think it is clear that HIV-positive patients should be included in CAR-T clinical trials.”

‘Don’t ask, don’t tell’

None of the commercially available CAR-T products indicated for large B-cell non-Hodgkin lymphoma are specifically licensed for use by people with HIV, Noy said.

“But some manufacturers look the other way,” she added. “It’s a matter of ‘don’t ask, don’t tell.’”

No safety issues arise from the manufacture of CAR T cells from individuals with HIV, Noy said. Previous experiments have shown the HIV virus cannot replicate from autologous cells used during T-cell expansion — part of the CAR-T manufacturing process — which is done in a controlled environment, she added.

Novartis produces tisagenlecleucel (Kymriah), a CD19-directed CAR-T for treatment of adults with relapsed or refractory B-cell non-Hodgkin lymphoma.

A company spokeswoman told Healio | Cell Therapy Next the safety and efficacy of tisagenlecleucel has not been confirmed among individuals with HIV and that apheresed cells from those with active HIV infection will not be accepted for the manufacturing of the therapy.

There are clinically known risks [for] disease reactivation for patients with HIV related to immunosuppression and depletion of B cells that have been reported among patients who have received chemotherapy or anti-CD20 antibodies, Novartis said in a statement.

The approach Novartis has taken on this issue is outdated, especially against a backdrop of effective treatments, Barta said.

“People living with HIV have been able to successfully undergo both autologous and allogeneic hematopoietic [stem] cell transplants in the era of modern anti-retroviral therapies,” Barta said. “Further, the expert consensus has been that people living with well-controlled HIV can safely undergo high‐dose therapy — including CD20‐directed therapy — without significantly increased risk.”

Kite Pharma markets the CD19-directed CAR-T axicabtagene ciloleucel (Yescarta) for adults with relapsed or refractory large B-cell non-Hodgkin lymphoma.

Treatment with axicabtagene ciloleucel is not restricted according to HIV status and is done at the discretion of the treating physician, a Kite spokeswoman told Healio | Cell Therapy Next.

The FDA label for axicabtagene ciloleucel advises physicians “perform screening for ... HIV and management in accordance with clinical guidelines before collection of cells for manufacturing.”

Bristol Myers Squibb manufactures lisocabtagene maraleucel (Breyanzi), a CD19-directed CAR-T for relapsed or refractory large B-cell non-Hodgkin lymphoma or those who have early relapse after first-line chemoimmunotherapy. Company officials declined a request for comment.

The lack of precise guidance — coupled with scant research — has led some insurance providers to deny coverage of commercial CAR-T products, Barta said.

“Sometimes we’ve had issues with insurances not approving therapy because patients with HIV were not included in the registrational [CAR-T] trials,” he said.

Boro Dropulić, PhD, MBA — co-founder and executive director of Caring Cross, a nonprofit organization that aims to improve access to advanced medicines for underserved populations — is a trained virologist who has more than 3 decades of experience in gene and cell therapy. He also has expertise in CAR-T development and manufacturing.

He said he is unaware of any safety issues related to the manufacturing process when using cells from people with HIV.

“I don’t see any issues for manufacturing CAR-T cells from people with HIV. CAR-T cell products are manufactured using disposable closed systems, so issues like cross-contamination should not be a concern,” Dropulić told Healio | Cell Therapy Next. “If individuals maintain their antiretroviral drug therapy during the course, then I believe that they should be treated in the same way as any individual receiving CAR T cells as standard care.”

Filling the gap

Despite a history of exclusion and the ambiguity among commercial manufacturers, Dropulić said he believes trial sponsors will begin to realize the value of including more diverse populations in their studies — particularly later-phase research.

“It’s very important that people with HIV get access to the most cutting-edge therapies available, first under a clinical trial and then access to the therapy after approval,” Dropulić said. “People with HIV and lymphoma are an important population that needs to be addressed.”

His organization is involved in several trials to develop CAR-T candidates and their manufacturing processes in partnership with hospitals, with the aim of producing therapies at the point of care rather than at centralized facilities.

One of the goals is to develop CAR T-cell therapies for patients with HIV and lymphoma, although none are yet in clinical testing.

Referring physicians still could use a knowledge refresh on HIV management and what is possible in terms of cancer treatment for those who have well-controlled disease, Noy said.

Barta agreed, adding education is the first step to gaining full access to CAR-T for people with HIV, now that preliminary evidence suggests it is safe and equally effective for this population.

“It’s the responsibility of leaders in the field and experts at larger hospitals to lead these educational efforts,” he said. “Groups such as the AIDS Malignancy Consortium ... can fill that gap to make sure people are not left behind because of their HIV status.”

‘A true travesty’

There is near-consensus in the cell therapy community about the need to liberalize clinical trial exclusion criteria to help expand access to CAR-T for people living with HIV.

Barta and Noy referred to the ASCO-Friends of Cancer Research HIV Working Group recommendations for modernizing clinical trial eligibility criteria, published in 2017 in Journal of Clinical Oncology.

“HIV infection itself should no longer be an exclusion criterion for most studies,” Uldrick and colleagues wrote in their recommendations.

“Criteria should not be more stringent than for HIV-uninfected patients with the same disease or treatment history,” they added.

Barta agreed with the group’s overall conclusions and said HIV infection should be viewed as a comorbidity rather than a blanket exclusion criterion in the context of clinical trial selection.

“We wouldn’t put anybody with uncontrolled heart failure on a clinical trial, which makes total sense,” Barta said. “Likewise, we shouldn’t put anybody with uncontrolled infections — and that includes HIV — on a clinical trial because we want to make sure that safety is still our first concern.”

Despite the working group’s recommendations, many trials — particularly those evaluating immune-oncology agents — still exclude people living with HIV. These trials tend to have rather unrealistic inclusion criteria, such as relatively high CD4 counts, Barta said.

Noy, part of the working group, lamented the lack of progress regarding implementation of the recommendations.

“I was so proud of that when we did it, and I felt really privileged to have the opportunity to make an impact on people’s lives,” she said. “It has been a true travesty that these efforts have not led to any changes.”

Not all people living with HIV will qualify for a CAR-T trial or standard treatment; however, participation should be based on overall patient biology rather than HIV status or any other single factor, Noy said.

AMC is taking this approach in its upcoming prospective study — AMC-112 — which will examine the safety and efficacy of axicabtagene ciloleucel among adults with HIV and relapsed or refractory B-cell non-Hodgkin lymphoma.

The trial — cosponsored by NCI and Kite Pharma — will be the first phase 1 prospective study of CAR-T to include patients with HIV.

Exclusion criteria will be based on biologically relevant factors and account for many of the recommendations of the working group, said Noy, an AMC member.

“We will ask the questions that matter,” she said.

They will include whether a patient has had recent opportunistic infection, establishing a reasonable and safe viral load limit for participation, and assessing whether a prospective enrollee is adhering to his or her antiretroviral regimen.

“The answers to these questions can predict exceptionally poor outcomes with cancer therapy for patients with HIV, so it doesn’t make sense for us to include all patients with HIV in our study,” Noy said. “However, these are all biologic questions and none of them will be discriminatory.”

References:

• Barta SK, et al. Abstract 763. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
• Engles EA, et al. Clin Infect Dis. 2017;doi:10.1093/cid/cix392.
• Horner MJ, et al. Clin Infect Dis. 2021;doi:10.1093/cid/ciaa1016.
• Uldrick TS, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2017.73.7338.
• Yescarta [prescribing information]. Santa Monica, CA: Kite Pharma Inc.; 2022.

For more information:

Stefan K. Barta, MD, can be reached at stefan.barta@pennmedicine.upenn.edu.

Boro Dropulić, PhD, MBA, can be reached at boro.dropulic@caringcross.org.

Ariela Noy, MD, can be reached at noya@mskcc.org.

Paul A. Volberding, MD, can be reached at paul.volberding@ucsf.edu.