Among the neglected tropical diseases, leishmaniasis continues to be prevalent in many tropical and subtropical countries despite international, national, and local efforts towards its control and elimination over the last decade. This warrants a critical evaluation of such factors as under-reporting, asymptomatic infections, post kala azar dermal leishmaniasis (PKDL) cases, and drug resistance. In this review, we highlight lesser-understood atypical presentations of the disease involving atypical parasite strains against a background of classical leishmaniasis with a focus on the Indian subcontinent. A literature review based on endemic areas, the nature of disease manifestation, and underlying causative parasite was performed with data collected from WHO reports for each country. Searches on PubMed included the term ‘‘leishmaniasis” and “leishmaniasis epidemiology” alone and in combination with each of the endemic countries, Leishmania species, cutaneous, visceral, endemic, non-endemic, typical, classical, atypical, and unusual with no date limit and published in English up to September 2017. Our findings portray a scenario with a wider distribution of the disease in new endemic foci, with new discoveries of parasite-driven atypical disease manifestations in different regions of the world. Unlike the classical picture, some Leishmania species are associated with more than one disease presentation, e.g., the L. donovani complex, generally associated with the visceral form, is now also associated with a cutaneous disease presentation, while L. tropica species complex, known to cause cutaneous disease, can cause viscerotropic disease. This phenomenon points towards the discovery of novel parasite variants as etiologic agents of atypical disease manifestations and represents an excellent opportunity to identify and study genes that control disease virulence and tropism. The increased recognition of atypical leishmaniasis as an outcome of parasite variants has major implications for leishmaniasis control and elimination. Identifying molecular correlates of parasite isolates from distinct regions associated with different disease phenotypes is required to understand the current epidemiology of leishmaniasis in regions with atypical disease.

Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy.

Leishmania donovani with Atypical Cutaneous Manifestations, Himachal Pradesh, India, 2014–2018

Leishmaniasis is a neglected tropical disease endemic in over 90 countries. The disease has two main pathologies; cutaneous leishmaniasis (CL) that generally self-heals, and visceral leishmaniasis (VL) that is fatal if untreated. The majority of VL cases, concentrated on the Indian subcontinent (ISC) and East Africa, are caused by Leishmania donovani. However, recent foci of CL on the ISC have been attributed as an atypical phenotype of L. donovani including a recent outbreak in Himachal Pradesh, India. Whole genome sequencing and phylogenetic analysis was undertaken to investigate the origins and genetic factors leading to this pathology atypical of L. donovani. Here we demonstrate the isolate from Himachal Pradesh is derived from a genetic hybridization between two independent L. donovani parents from the ‘Yeti’ ISC1 divergent clade of parasites, identified in the Nepalese highlands. This reveals that intraspecies L. donovani hybrids can give rise to a novel strain associated with CL.

Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system’s response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host’s miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.

Himachal Pradesh in India is a newer endemic state with co-existence of cutaneous and visceral leishmaniasis. The cutaneous leishmaniasis cases are on an increase in the region and reported to be unusually caused by Leishmania donovani with limited molecular validation. In order to molecularly characterize the causative parasite of the cutaneous disease, parasite specific Internal-Transcribed Spacer 1 (ITS1) PCR RFLP and sequence analysis was performed on skin lesional biopsies from cutaneous leishmaniasis patients. Interestingly, we found the presence of Leptomonas seymouri in 38.5% (22/57) of the patients along with L. donovani detected in all the samples. L. seymouri is a monoxenous insect trypanosomatid, generally incapable of infecting humans. In recent years, the parasite is also reported to co-infect humans with L. donovani in visceral and post kala-azar dermal leishmaniasis (PKDL) cases prevalent in northeastern India. The finding of L. seymouri-L. donovani co-infection in unusual cutaneous cases from Himachal Pradesh is the first ever to our knowledge and imply a newer disease paradigm. There is an urgent need to understand the biology of Leptomonas co-infection with L. donovani and its possible role in visceral and/or dermotropic disease outcome. Importantly, L. seymouri co-infection in cutaneous cases and previously reported visceral and PKDL cases needs to be recognized as a newer phenomenon by the leishmaniasis surveillance program in India.