Cancer is a global health crisis affecting millions of people worldwide. However, developing countries often face the challenge of limited access to cutting-edge cancer care. This begs the question: how long must they wait for the latest advancements in cancer treatment? It is time for us to address this issue and work towards providing equal access to lifesaving cancer care across the globe.

Although the incidence of cancer and cancer-related mortality has been historically higher in high-income countries (HICs) compared with low- and middle-income countries (LMICs), current trends point to a gradual increase in LMICs, suggesting potential underdiagnosis in these regions.1 Similarly, the survival rate for most cancers in LMICs is significantly lower than in HICs, mainly due to late diagnosis and lack of access to advanced treatment options.2

CAR-T (chimeric antigen receptor T-cell) therapy, which involves reprogramming patients’ T cells with a CAR to enable precise targeting and killing of cancer cells, represents a groundbreaking advancement in cancer treatment.3–8 This innovative approach is gaining momentum, particularly in HICs. The cost of CAR-T therapy can be prohibitively high for LMICs that often grapple with limited resources, infrastructure challenges, and a high absolute burden of cancer cases. As a result, access to advanced cancer treatment remains out of reach for many individuals in these regions.

So far, research and development of CAR-T has been concentrated in HICs. However, there is an urgent need to make CAR-T therapy available to LMICs. Understanding its importance in the context of these countries requires exploring its unique characteristics and addressing the specific needs of the local population. The significance of CAR-T therapy in LMICs stems from several factors, with its potential for high efficacy in treating certain types of cancer being foremost among them. Currently, many LMICs rely primarily on traditional treatments like chemotherapy and radiation therapy, which can have significant side effects and may not always yield durable responses.

On the other hand, CAR-T therapy offers the promise of prolonged remission, and, in some cases, even cures where conventional therapies have been ineffective. Furthermore, CAR-T therapy can be particularly relevant in LMICs where prevalent cancers, such as certain types of lymphomas and leukemias, are more responsive to this targeted approach. The ability to tailor treatment to the patient’s specific cancer profile enhances its effectiveness, making it an attractive option for diseases that may be resistant to standard therapies.

In LMICs, where access to advanced medical facilities and expertize may be limited, CAR T therapy’s relatively short treatment duration is advantageous. Traditional cancer treatments often require prolonged hospital stays and extensive follow-up, posing logistical challenges in regions with constrained healthcare infrastructure. CAR-T therapy offers a promising treatment option for patients with advanced cancer as it can be administered in a single infusion with limited hospitalization. This can reduce the burden on healthcare systems and make it a viable option for patients. However, despite its potential benefits, the lack of availability of this treatment in LMICs remains a major obstacle, preventing many patients from accessing it.

Integrating CAR-T therapy into LMICs presents significant challenges. A primary hurdle is the high cost associated with CAR-T cell development, production, and administration, coupled with the need for comprehensive regulatory guidelines (figure 1). These expensive therapies often remain inaccessible to many patients in resource-constrained settings. In countries like Nepal, regulatory bodies frequently lack adequate training and current knowledge about advanced treatments, including CAR-T cell therapy for patients with cancer. This knowledge gap results in prolonged approval processes, further limiting patient access to these innovative treatments and discouraging research and innovation efforts in the country.

Challenges to the production of chimeric antigen receptor (CAR) T cells for therapeutic use in Nepal. Hurdles to the CAR-T cell program in Nepal include manufacturing logistics, gaining access to advanced technologies for manufacturing quality CAR lentiviral particles, educating regulatory bodies, clinicians, and scientific personnel, and ensuring access to tertiary cancer care centers with advanced capabilities for cancer care. GMP, Good Manufacturing Practices LMIC, low- and middle-income country.

Moreover, local clinicians and scientists often lack specialized training in CAR-T therapy, leaving them unprepared to effectively administer infusion services and manage its clinical aspects. To address this challenge, continuous medical education-based training sessions focusing on advanced CAR-T therapy and post-care patient management will be periodically organized in Kathmandu, Nepal. These sessions will feature international clinical and scientific experts to enhance local capacity and expertize in CAR-T therapy.

In 2023, we organized a 2-day conference on cellular therapy in Kathmandu, Nepal, which was well-attended by Nepalese clinicians, scientists, regulatory bodies, and government officials. The conference highlighted the importance of CAR-T as an emerging treatment option for malignancies and autoimmunity, the potential for manufacturing it in local settings for low-cost availability in LMICs, educating/developing cell and gene therapy regulatory framework, seeking collaboration with international organizations like the National Institute of Health, National Cancer Institute, Leibniz Institute of Immunotherapy and providing advanced training to local man powers involved in CAR-T manufacturing, treatment and managing toxicities. While some well-off individuals are advised by clinicians to seek treatment in countries like China and India, the burden disproportionately falls on the poor, who cannot afford the high costs of these treatments and often die prematurely due to lack of access to advanced care. Government institutions must act swiftly to address this cost barrier and ensure equitable access to cancer care. They need to create a conducive environment and allocate resources for the indigenous production of CAR-T therapy. This step is essential to democratize access to this groundbreaking treatment and reduce disparities in cancer care outcomes in Nepal.

The Center for Regenerative Medicine in Nepal (CRM-Nepal) has taken the initiative to develop advanced cancer treatment for the Nepalese population and to establish a centralized GMP-compliant manufacturing unit in Kathmandu, Nepal. A centralized manufacturing and distribution platform model (D) will be adopted. Patients at cancer centers undergo leukapheresis, and the apheresis product is transferred to a manufacturing site for the specific product. The specific product is manufactured following uniform standard operating procedures and virus supernatant from a central charge for CAR gene engineering. The product is transferred back to the hospital/trial site where it is administered, and the patient is managed and followed up.8 Regarding T-cell expansion and B-cell aplasia analysis, patient peripheral blood will be harvested at several time points post-adoptive transfer. Flow cytometry will be used to detect the frequencies of circulating B cells. Digital droplet PCR will be performed to quantify the amount of CAR transgenes in patient blood samples.

As a first step, here we report and characterize the production of CD19 CAR-T cells from healthy donor T cells, serving as a feasibility study to assess local laboratory capabilities using reagents sourced locally or from other countries like India (CAR-T media, interleukin-2 (IL-2), activation beads) and USA (antibodies and CAR plasmids/lentiviruses). To enable CAR-T cell manufacturing locally, we utilized G-Rex platforms to facilitate T-cell expansion on a larger scale and minimize hands-on time. The experiments included CD3+ cell selection, lentiviral transduction, and T-cell expansion using IL-2 (figure 2). Three of three CAR-T cell products manufactured met the full list of specifications and were considered valid products. They demonstrated CAR positivity anywhere from 25% to 58% (figure 2). All products obtained exhibited cytotoxic activity against CD19+ cells and were proficient in the secretion of pro-inflammatory cytokines, such as interferon-gamma (figure 2). Expansion kinetics and product potency were comparable across donors (figure 2).

Functional characterization of CAR-T cells. Left panel, representative flow cytometry plot showing expressions of CD19 CAR post-transduction of activated CD3+ T cells. Center panel, bar diagrams showing the killing of CD19 NALM6 cells by CD19 CAR-T cells (effector to tumor ratio 1:1) in 24 hours co-culture assay. Right panels, bar diagrams showing interferon-gamma produced by CAR-T cells in the supernatant obtained from coculture assays. The benchmark used is CAR-T cells that express the “Kymriah” single chain variable fragment (scFv) sequence. Internal CAR asset is a second-generation molecule with 41-bb as a costimulatory domain. CAR, chimeric antigen receptor, scFv, single chain variable fragment, SSC, side scatter.

This preclinical study demonstrates the feasibility of implementing CAR-T cell therapy in Nepal. Currently, CRM-Nepal is in the process of constructing two GMP-complaint manufacturing facilities in Kathmandu, Nepal. While the production will be run on a not-for-profit basis with support from the government, hospitals, private sectors, and academic centers, the estimated cost per patient is approximately US$40,000. Most of the cost is attributed to reagents procured from developed countries, as well as from China and India. The detailed and precise manufacturing cost will be determined once the team is closer to operating the GMP units for clinical manufacturing. CRM-Nepal has planned to train nursing staff and critical care clinicians in the critical care unit on established protocols for managing patients who display potential CAR T-cell-related toxicities. In brief, the following CAR-T cell-related toxicities will be managed as follows: (1) Cytokine release syndrome (CRS) management: CRS is a common and potentially severe side effect of CAR T-cell therapy. Management typically will involve using tocilizumab and corticosteroids to mitigate the inflammatory response. (2) Neurotoxicity management: Immune effector cell-associated neurotoxicity syndrome is another significant concern. Management strategies will include close monitoring of neurological symptoms and corticosteroids if necessary. (3) Hematologic toxicity: Hematologic toxicities, such as neutropenia and thrombocytopenia, will be managed through supportive care, including growth factor support and transfusions, and (4) Standardized guidelines: Standardized guidelines for managing CAR T-cell therapy-related toxicities will include intensive care unit admission protocols, monitoring vital signs, and using supportive care measures.

These facilities will pave the way for advanced cancer treatment research and the developing of domestic CAR T production for cancer and other diseases.

Consent obtained directly from patient(s).

This study involves human participants and was approved by Nepal Health Research Council (Reference number: 1033). Participants gave informed consent to participate in the study before taking part.

We are grateful to DECODE Genomics and Research Centre, Kathmandu, Nepal, for providing laboratory facilities for the preclinical work. We thank Professor Luca Gattinoni, Leibniz Institute of Immunotherapy, Regensburg, Germany, for his suggestions on this commentary.