Latin America and evolving oncotherapeutics using CAR T cells, conjugated antibodies, and bispecific antibodies Open Access

TO THE EDITOR:

Physicians, worldwide, constantly anticipate the publication of groundbreaking reports that might improve outcomes for patients with life-threatening conditions. As hematologists, we focus on novel biologic agent–based anticancer therapeutics, such as chimeric antigen receptor T-cell (CAR-T) therapies, conjugated antibodies, and bispecific antibodies, which are revolutionizing treatments for hematologic malignancies. However, our enthusiasm for these advancements is tempered by the undeniable reality of limited global access. Here, we provide context on the current status of innovative treatments and the challenges in providing access to these therapies within Latin America (LATAM).

LATAM encompasses more than 20 nations in the Western hemisphere, unified by language (predominantly Spanish) and cultural traditions, but with widely varying economic disparities and health care infrastructures.¹ Each country has its own regulatory framework, often coupled with fragmented health care systems across public and private sectors.^1,2 Marked country-to-country differences in health care resources and delivery systems affect the availability and applicability of therapies using CAR-Ts, conjugated antibodies, and bispecific antibodies. Thus, implementing these therapies requires an understanding of each country’s economic and health care infrastructure challenges and opportunities.

Commercially available CAR-Ts have demonstrated high efficacy in treating hematologic cancers, such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma, and, more recently, multiple myeloma (MM).^3-5 However, their high costs and logistical complexities (including production, distribution, and administration) create significant barriers to widespread adoption in LATAM. Countries with established hematopoietic stem cell transplantation programs (HSCTP) and access to Good Manufacturing Practices (GMP) facilities are better positioned to implement CAR-T therapies. Although CAR-T administration should take place within HSCTPs to optimize outcomes, the GMP facility does not need to be nearby. For efficiency and cost saving, centralizing cell production at experienced GMP facilities within a LATAM country/region is preferable, with subsequent distribution to relevant HSCTPs.

Although the clinical infrastructure requisite to deliver cell-based therapies is generally underdeveloped in LATAM countries, according to the Latin America Bone Marrow Transplantation Group, 14 LATAM countries host 271 active HSCTPs, with Argentina, Mexico, and Brazil having >30 each.⁶ Despite this encouraging statistic, a paradox exists: countries with the highest HSCT rates often conduct these procedures in private hospitals with predominantly private funding and higher costs.⁷ This economic disparity limits broader access of HSCT and CAR-Ts, particularly in nations with primarily public health care systems.

The affordability of CAR-Ts is a fundamental hurdle in LATAM. For instance, Argentina has sufficient medical facilities but faces significant economic challenges, including high inflation, a weakening currency, and increasing public debt. According to the World Bank, Argentina’s gross domestic product per capita is 13 730 US dollars (USD) compared to 81 695 USD in the United States. With a median annual CAR-T therapy cost of 450 000 USD, more than 32 times Argentina’s gross domestic product per capita, these treatments would remain inaccessible for most.⁸ 

Beyond affordability, the regulatory frameworks within LATAM countries for introducing novel therapeutics hinder their adoption. Although some LATAM countries participate in clinical trials using CAR-Ts (eg, Argentina for MM), bureaucratic challenges in regulatory approvals persist.

Currently, Brazil is the only LATAM country with regulatory approval for using CAR-Ts in treating B-cell malignancies and MM. Approved products include tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta), and ciltacabtagene autoleucel (Carvykti). However, implementation in Brazil faces significant financial challenges due to the high costs of manufacturing, administration, and managing therapy-related side effects. Limited access to specialized care centers further exacerbates these barriers.

Academic CAR-T development is progressing in Brazil and Mexico. In Brazil, anti-CD19 CAR-Ts are available in clinical trials⁹ and B-cell maturation antigen (BCMA)-targeting CAR-Ts for MM are in development. In Mexico, anti-CD19 CAR-Ts are also being developed and are awaiting authorization for clinical trial enrollment.

Several conjugated antibodies have been approved in LATAM. Inotuzumab ozogamicin (Besponsa) is approved for relapsed/refractory (RR) CD22⁺ ALL in Argentina, Chile, Brazil, and Mexico. The anti-BCMA conjugated antibody belantamab mafodotin (Blenrep) is undergoing clinical trials for RRMM in Argentina and Brazil. Polatuzumab vedotin (Polivy), combined with chemotherapy, has recently been approved for diffuse large B-cell lymphoma in Argentina, Brazil, Colombia, and Mexico.

In terms of bispecific antibodies, blinatumomab (Blincyto; anti-CD19/anti-CD3) is approved in 8 LATAM countries for RR CD19⁺ ALL. Epcoritamab (Epkinly; anti-CD3/anti-CD20) is approved in Argentina, Brazil, and Mexico for relapsed diffuse large B-cell lymphoma. For RRMM, teclistamab (Tecvayli; anti-CD3/BCMA) is recently approved in 8 countries and talquetamab (Talvey; anti-CD3/GPRC5D) is approved in Brazil and Mexico; Brazil remains the only LATAM country with regulatory approval for elranatamab (Elrexfio; anti-CD3/BCMA). Table 1 summarizes the current availability of cellular and biologic agent immunotherapies directed to hematologic malignancies.

Though the information in Table 1 may suggest that pertinent clinical outcomes are being reported, data on the efficacy of delivered cellular and biologic agents in LATAM are sparse. For example, there are no publications reporting experience(s) in use of these novel therapies in Argentina. However, recent scientific findings presented at the 2023 Argentinian Hematology Society Congress reported clinical outcomes comparable to global data for blinatumomab and inotuzumab ozogamicin in RR ALL^10,11 but lower response rates for elranatamab in RRMM.^12,13 

Despite these multiple factors that altogether result in great inequalities in access to specialized medical care and cutting-edge treatments within LATAM, opportunities exist for innovative strategies to drive forward public-private collaborations, coupled with accessible financing and professional training initiatives, which could overcome current economic and geographic barriers. Public-private partnerships could streamline interactions between pharmaceutical industry personnel, clinicians, and regulators, potentially easing economic hurdles. In particular, the conventional high pricing model of the biotech/pharmaceutical industry, a model in which cost of treatment far exceeds production costs, is often justified by associated research and developmental expenses requisite to the creation and implementation of the pertinent therapy. If true that developmental costs justify such high pricing models, many of these costs could be offset by governmental subsidies and/or charitable foundation support within the relevant developmental period of the proposed pertinent therapeutic approach. For example, in the United States, the National Institutes of Health frequently provides funding to de-risk novel therapies, validating their concept and applicability to enhance marketability.

Interinstitutional collaborations within LATAM medical centers, coordinated and subsidized by governmental agencies, could help improve the accessibility of cell-based therapies. For example, in Spain, the publicly-funded TeraV network includes 51 academic institutions and hospitals, aiming to develop validated cell therapies through decentralized, academic point-of-care manufacturing under strict GMP guidelines.¹⁴ Under hospital exemption regulations, the Spanish regulatory agency oversees academic point-of-care cell production and administration in multicenter trials to ensure quality, safety, and efficacy.¹⁵ 

Still, there are high costs associated with clinical trials (and the attendant regulatory pathways) that are not supported by governmental or foundation funds. But, here, we submit that the lower costs of clinical trials in LATAM countries offer an opportunity to diminish the associated developmental costs. In our view, including LATAM patients early in clinical trials (especially phase 1 and phase 2a clinical trials) could provide several benefits to improve the infrastructure for the development of cell-based therapies and to promote greater accessibility: it would enhance the local/regional expertise regarding the biomedical science of the pertinent cell therapy and evaluation of its efficacy across diverse populations; it would promote local public-private partnerships that could potentially reduce costs for regional patients; and it would increase the awareness and experience of clinical providers within LATAM countries and their respective regions to the proposed life-saving therapeutic options.

The highly qualified medical talent and renowned research centers in LATAM could play a pivotal role in adapting therapies to local needs and to their subsequent sustainability. Collaboration between the pharmaceutical industry, academic institutions, and health authorities is essential to foster research and implementation of advanced therapies in any region, let alone LATAM.

In summary, although CAR-Ts, conjugated antibodies, and bispecific antibodies represent significant advancements in treating hematologic cancers, their implementation in LATAM faces challenges in accessibility and sustainability. However, their potential to markedly improve human welfare both inspires and justifies the creation of public-private collaborative efforts to overcome these barriers and ensure availability for all patients in the Western hemisphere.

Contribution: R.S. and P.J.D. wrote the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Patricio J. Duarte, Division of Hematology, Centro de Educación Médica e Investigaciones Clínicas University Hospital, 4102 Galvan Ave, Buenos Aires, C1431FWO Argentina; email: pduarte@iuc.edu.ar.