Evolving Paradigms in HIV Malignancies: Review of Ongoing Clinical Trials

Abstract

This review highlights current interventional clinical trials for HIV-associated malignancies (HIVAMs), with emphasis on 4 mechanistic areas: immunomodulatory therapies and gene therapies, including immune checkpoint inhibitors; cytotoxic therapies; novel tumor-targeted and virally targeted therapies in both AIDS-defining and non–AIDS-defining cancers (NADC); and other screening or topical/ablative interventions. A search on ClinicalTrials.gov located 35 trials, including 12 immunomodulatory or gene therapy trials, 6 cytotoxic therapy trials, 10 trials of therapies with tumor or viral molecular targets, and 7 trials evaluating screening interventions or topical or ablative therapies. Study drugs, mechanisms, and outcomes of interest, including future directions, are discussed. Targeted therapies and immunotherapies address not only the tumor but underlying viral oncogens, including possible benefits on HIV-specific immunologic control. The resulting science from the trials listed in this review will provide important translational breakthroughs for people living with HIV (PLWH) and cancer. We highlight disease-specific challenges that could be addressed in future studies, including testing the safety and efficacy of cutting-edge immunotherapy and targeted treatments used in the general cancer population, and improving gaps in knowledge and practice for cancer screening and its treatment, especially in low-resource regions. Additional important considerations include identification of novel therapies for virally mediated tumors that disproportionally present in PLWH, how to treat persons with HIVAM and advanced immunosuppression, and how to comanage both diseases in antiretroviral therapy–naïve persons and those receiving care in settings where supportive therapies for hematologic toxicities and infections are limited. Current and future clinical trials should address needs of both resource-replete and -limited regions, as well as cancers that are uncommon in or respond differently to HIV-negative populations (eg, Kaposi sarcoma or anal cancer), in addition to an increased focus on NADCs not traditionally linked with HIV, such as lung or gastrointestinal tumors.

Immunotherapy in People With HIV and Cancer

“…In HIV-associated B cell NHL, reduced T-cell polyfunctionality and TCR diversity is associated with poorer prognosis (61). These observations, among others (62), have led to interest in remedying immune dysfunction to treat malignancy in PLWH (63).…”

The Role of Immunomodulatory Receptors in the Pathogenesis of HIV Infection: A Therapeutic Opportunity for HIV Cure?

“…Patients with HIV infection were generally excluded from the clinical trials with immune checkpoint blockade, because of the safety concerns and the potential adverse outcomes (259)(260)(261)(262). Case reports and clinical trials focusing on various types of malignancies for HIV infected patients started to emerge since 2017 (218,(263)(264)(265)(266)(267)(268)(269)(270)(271)(272)(273).…”

Review: The Impact of HIV Infection on Cancer Treatment with Immunotherapy

“…In an attempt to explore this opportunity, the Friends of Cancer Research HIV Working Group showed that 74% of studies leading to the Food and Drug Administration (FDA) approval for cancer treatments excluded patients with HIV specifically or those with infection generally. [25] This has led to the design of multiple Liver, renal, bone marrow toxicity Examine tendency of oncologists, overall, to provide lower doses, shorter duration, lower threshold to stop treatment [16] Recent NCCN Guidelines for multiple diseases [6]…”

“…Small studies of allogeneic transplant suggest feasible and safe Fewer drug-drug interactions Prolonged immunosuppression with CD4 count suppressed up to a year, [21] increases risk of opportunistic and other infections Potential for HIV cure, with allogeneic transplant from patient with CCR5∆32 mutation, which inactivates the CCR5 receptor gene [22][23][24] ART: Antiretroviral therapy, CAR: Chimeric antigen receptor, CRES: CAR T-cell-related encephalopathy syndrome, NCCN: National Comprehensive Cancer Network, HIV: Human immunodeficiency virus, VA: Veterans affairs clinical trials targeting HIV-associated malignancies and other cancers in patients with HIV. [25] These studies emphasize immunotherapy and targeted therapy, as opposed to traditional cytotoxic chemotherapy approaches. These clinical trials will provide important information regarding the safety and effectiveness of immunotherapy in patients with HIV and cancer.…”

“…The potential benefits of ICIs in the treatment of HIV have led to clinical trials, mentioned previously, to determine their utility in overcoming "immune exhaustion" of chronic HIV infection, manifested by persistently low CD4 count, despite viral suppression. Although clinical trials with ICIs for the treatment of cancer excluded patients with HIV, [25] recent retrospective studies have examined the benefit of ICIs in cancer patients with HIV. Given that HIV itself and smoking exposure lead to increased PD-L1 expression, [38] PD-1 shows a particular promise.…”