Next-generation treatments: Immunotherapy and advanced therapies for COVID-19.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in 2019 following prior outbreaks of coronaviruses like SARS and MERS in recent decades, underscoring their high potential of infectivity in humans. Insights from previous outbreaks of SARS and MERS have played a significant role in developing effective strategies to mitigate the global impact of SARS-CoV-2. As of January 7, 2024, there have been 774,075,242 confirmed cases of COVID-19 worldwide. To date, 13.59 billion vaccine doses have been administered, and there have been 7,012,986 documented fatalities (https://www.who.int/) Despite significant progress in addressing the COVID-19 pandemic, the rapid evolution of SARS-CoV-2 challenges human defenses, presenting ongoing global challenges. The emergence of new SARS-CoV-2 lineages, shaped by mutation and recombination processes, has led to successive waves of infections. This scenario reveals the need for next-generation vaccines as a crucial requirement for ensuring ongoing protection against SARS-CoV-2. This demand calls for formulations that trigger a robust adaptive immune response without leading the acute inflammation linked with the infection. Key mutations detected in the Spike protein, a critical target for neutralizing antibodies and vaccine design -specifically within the Receptor Binding Domain region of Omicron variant lineages (B.1.1.529), currently dominant worldwide, have intensified concerns due to their association with immunity evasion from prior vaccinations and infections. As the world deals with this evolving threat, the narrative extends to the realm of emerging variants, each displaying new mutations with implications that remain largely misunderstood. Notably, the JN.1 Omicron lineage is gaining global prevalence, and early findings suggest it stands among the immune-evading variants, a characteristic attributed to its mutation L455S. Moreover, the detrimental consequences of the novel emergence of SARS-CoV-2 lineages bear a particularly critical impact on immunocompromised individuals and older adults. Immunocompromised individuals face challenges such as suboptimal responses to COVID-19 vaccines, rendering them more susceptible to severe disease. Similarly, older adults have an increased risk of severe disease and the presence of comorbid conditions, find themselves at a heightened vulnerability to develop COVID-19 disease. Thus, recognizing these intricate factors is crucial for effectively tailoring public health strategies to protect these vulnerable populations. In this context, this review aims to describe, analyze, and discuss the current progress of the next-generation treatments encompassing immunotherapeutic approaches and advanced therapies emerging as complements that will offer solutions to counter the disadvantages of the existing options. Preliminary outcomes show that these strategies target the virus and address the immunomodulatory responses associated with COVID-19. Furthermore, the capacity to promote tissue repair has been demonstrated, which can be particularly noteworthy for immunocompromised individuals who stand as vulnerable actors in the global landscape of coronavirus infections. The emerging next-generation treatments possess broader potential, offering protection against a wide range of variants and enhancing the ability to counter the impact of the constant evolution of the virus. Furthermore, advanced therapies are projected as potential treatment alternatives for managing Chronic Post-COVID-19 syndromeand addressing its associated long-term complications.

Anti-ROR1 CAR-T cells: Architecture and performance.

The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a membrane receptor that plays a key role in development. It is highly expressed during the embryonic stage and relatively low in some normal adult tissues. Malignancies such as leukemia, lymphoma, and some solid tumors overexpress ROR1, making it a promising target for cancer treatment. Moreover, immunotherapy with autologous T-cells engineered to express a ROR1-specific chimeric antigen receptor (ROR1 CAR-T cells) has emerged as a personalized therapeutic option for patients with tumor recurrence after conventional treatments. However, tumor cell heterogeneity and tumor microenvironment (TME) hinder successful clinical outcomes. This review briefly describes the biological functions of ROR1 and its relevance as a tumor therapeutic target, as well as the architecture, activity, evaluation, and safety of some ROR1 CAR-T cells used in basic research and clinical trials. Finally, the feasibility of applying the ROR1 CAR-T cell strategy in combination with therapies targeting other tumor antigens or with inhibitors that prevent tumor antigenic escape is also discussed. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02706392.

CAR-T Cell Performance: How to Improve Their Persistence?

Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.

The novel HLA-A*30:172 allele identified in a donor from the Colombian bone marrow donor registry.

HLA-A*30:172 differs from HLA-A*30:01:01:01 by a single nucleotide in codon 153 in exon 3.

Characterization of the novel HLA-DRB1*04:315 allele by next-generation sequencing.

HLA-DRB1*04:315 differs from HLA-DRB1*04:07:01:02 by a single nucleotide substitution in codon 147 of exon 3.

Identification of a novel HLA-DRB1 null allele, HLA-DRB1*13:298N, in two siblings from Colombia.

Identification of a novel null allele, HLA-DRB1*13:298N, resulting from a deletion of two nucleotides.

Description of HLA-DRB1*14:02:09, a novel HLA allele identified in a Colombian donor.

HLA-DRB1*14:02:09 differs from HLA-DRB1*14:02:01:02 by a single nucleotide substitution in codon 169 of exon 3.

Identification of five novel HLA-B alleles in donors from the Colombian Bone Marrow Donor Registry.

Identification of five novel HLA-B alleles in five samples from Colombian bone marrow donors.

Distributions of the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 alleles and haplotype frequencies of 1763 stem cell donors in the Colombian Bone Marrow Registry typed by next-generation sequencing.

The HLA compatibility continues to be the main limitation when finding compatible donors, especially if an identical match is not found within the patient's family group. The creation of bone marrow registries allowed a therapeutic option by identifying 10/10 compatible unrelated donors (URD). However, the availability and frequency of haplotypes and HLA alleles are different among ethnic groups and geographical areas, increasing the difficulty of finding identical matches in international registries. In this study, the HLA-A, -B, -C, -DRB1, and -DQB1 loci of 1763 donors registered in the Colombian Bone Marrow Registry were typed by next-generation sequencing. A total of 52 HLA-A, 111 HLA-B, 41 HLA-C, 47 HLA-DRB1, and 20 HLA-DQB1 alleles were identified. The 3 most frequent alleles for each loci were A*24:02g (20,8%), A*02:01g (16,1%), A*01:01g (7.06%); B*35:43g (7.69%), B*40:02g (7.18%), B*44:03g (6.07%); C*04:01g (15.40%), C*01:02g (10.49%), C*07:02g (10.44%); DRB1*04:07g (11.03%), DRB1*07:01g (9.78%), DRB1*08:02g (6.72%); DQB1*03:02g (20.96%), DQB1*03:01g (17.78%) and DQB1*02:01g (16.05%). A total of 497 HLA-A-C-B-DRB1-DQB1 haplotypes were observed with a frequency greater than or equal to 0.05% (> 0.05%); the haplotypes with the highest frequency were A*24:02g~B*35:43g~C*01:02g~DQB1*03:02g~DRB1*04:07g (3.34%), A*29:02g~B*44:03g~C*16:01g~DQB1*02:01g~DRB1*07:01g (2.04%), and A*01:01g~B*08:01g~C*07:01g~DQB1*02:01g~DRB1*03:01g (1.83%). This data will allow the new Colombian Bone Marrow Donor Registry to assess the genetic heterogeneity of the Colombian population and serve as a tool of interest for future searches of unrelated donors in the country.

The novel HLA-A*24 allele, HLA-A*24:487, identified in three unrelated bone marrow donors in Colombia.

Identification of the novel HLA-A*24:487 allele, which differs from HLA-A*24:02:01:01 at one position.