• Cancer Immunotherapy
• Tuberculosis vaccine development
Summary of Research:
Protective Efficacy of MIP in Animal Models of Tuberculosis
Whole bacterial vaccines rely on multiple antigens and built-in-adjuvanticity. Mycobacterial strains which share cross-reactive antigens with M.tuberculosis are being considered as alternatives to M.bovis for vaccine use. Mycobacterium indicus pranii (MIP) shares antigens with M.tuberculosis and initial studies had shown that vaccination with killed MIP induces protection against tuberculosis. Hence, we further studied the protective potential of MIPand the underlying immune responses. This study aims to investigate the protective efficacy of MIP immunisation in live or killed form, through parenteral route as well as by aerosol immunization, against subsequent infection with M.tuberculosis in animal models. Study of immune response to M.tuberculosis in animals immunised with MIP. These responses are compared with those generated in BCG immunised mice.
The extended course of chemotherapy often results in poor compliance and the emergence of drug resistant strains. Therefore, improved therapeutic strategies are needed. Immunotherapy can boost protective immune responses and could contribute to the effective management of the disease when combined with chemotherapy. We sought to investigate whether MIP could be used as an adjunct to standard chemotherapy in guinea pig model of tuberculosis. The efficacy of MIP was evaluated when given by aerosol or parenteral route at sub acute or chronic stage of tuberculosis infection.
Immunotherapeutic Potential of MIP and the Underlying Mechanisms in Mouse Tumor Model
Role of the immune system in protecting the host from cancer is well established. The generation of antitumor immunity is often difficult in the tumor-bearing host because of various negative regulatory mechanisms. Activation of Innate and Th1 type immune response is important to overcome immunosuppression in the tumor-bearing hosts. There were indications from different clinical studies that MIP may be useful as an immunomodulatory adjunct in some cancers. In animal model of tuberculosis we had found that MIP induces Th1 type response, which is also important for antitumor activity. Hence, we sought to analyse the immunotherapeutic potential of MIP in mouse tumor model and the underlying mechanisms for its antitumor activity. Study of MIPas an adjunct to chemotherapy in combination with commercial anti cancer drug formulation in tumor bearing mice and simultaneous study of mechanism of MIP mediated host immune activation.
Combined chemo-immunotherapy strategies to combat cancer
It is well established that tumor suppresses the anticancer immune response at its local microenvironment to facilitate its growth, leading to cancer progression and metastasis. Immunotherapy, on the other hand, stimulates the immune system and helps to induce an effective anti-tumor response. Combined chemo-immunotherapy has multi faceted advantages. Chemotherapy induced cell death can enhance cross-priming of immune cells by providing them with important cancer specific antigens, thereby increasing the antitumor T cell response.
The prime objective of this study is to develop a combined chemo-immunotherapeutic formulations which could directly kill cancer cells as well as activate the suppressed tumor microenvironment to promote killing of tumor cells. Paclitaxel (PTX) and SP-LPS (non-toxic derivative of lipopolysaccharide) were selected as anti-cancer drug and immunostimulant respectively. We prepared a chemo-immunotherapeutic compound by conjugating a chemotherapeutic drug with an immune stimulant and also prepared nanoparticles co-encasulating both and their anticancer activity was evaluated. Further work with other polymers having macrophage stimulating property and antitumor activity is planned.
Mohd. Saquib, Ms. Bindu Singh, Ms. Ananya, Mr. Arvind Kumar
- Cell wall fraction of Mycobacterium indicus pranii shows potential Th1 adjuvant activity. Saqib, M., Khatri,R., Singh, B., Gupta,A., Bhaskar,S* (2019). International Immunopharmacology 70:408-416.
- Myeloid differentiation primary response protein 88 (MyD88)-deficient dendritic cells exhibit a skewed cytokine response to BCG. Kumar P and Bhaskar S* (2019). BMC Res Notes 12:52.
- Enhanced survival of BCG-stimulated dendritic cells: involvement of anti-apoptotic proteins and NF-kB. Kumar P, John V, Gupta A, Bhaskar S* (2018). Biology Open 7: bio032045.
- A unique vaccine with multiple applications. Talwar GP, Gupta JC, Krishnan AD, Mustafa AS, … Mukherjee R, Bhaskar S, Saini V, HasnainSE, Tyagi AK, Tyagi AK, Nandi D, Purswani S (2018) J Clin Exp Immunol 4:1-4.
- Mycobacterium indicus pranii protein MIP_05962 induces Th1 cell mediated immune response in mice. Sharma A, Saqib M, Sheikh J, Chaudhuri T, Bhaskar S, Ehtesham N, Hasnain S* (2018). International Journal of Medical Microbiology 308: 1000-1008.
- Autophagy induction by Mycobacterium indicus pranii promotes Mycobacterium tuberculosis clearance from RAW 264.7 macrophages. Bindu Singh, Mohd. Saqib, Ananya Gupta, Pawan Kumar, Bhaskar S* (2017). PLOS ONE. 12 (12), e0189606.
- Efficacy and Safety of Mycobacterium indicus pranii as an adjunct therapy in Category II pulmonary tuberculosis in a randomized trial. Sharma S*, Katoch K, Sarin R,…Bhaskar S, Rani R* (2017) Scientific Reports (7), 3354.
- Mycobacterium indicus pranii as a booster vaccine enhances BCG induced immunity and confers higher protection in animal models of tuberculosis Saqib, M., Khatri, R., Singh, B., Gupta, A., Kumar, A., Bhaskar S* (2016) Tuberculosis 101: 164e173.
- Pawan Kumar, Vini John, Soumitra Marathe, Gobardhan Das & Sangeeta Bhaskar (2015) Mycobacterium indicus pranii induces dendritic cell activation, survival and Th1/Th17 polarization potential in a TLR-dependent manner. J. of Leukocyte Biology 97: 511-520.
- Pawan Kumar, Rohit Tyagi, Gobardhan Das & Sangeeta Bhaskar (2014) Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll-like receptor-dependent manner. Immunology 143: 258-268.
- Manu Smriti Singh, Sangeeta Bhaskar (2014) Nanocarrier-based immunotherapy in cancer management and research. ImmunoTargets and Therapy 3:121-134.
- Aniruddha Roy, Manu Singh, Pramod Upadhyay & Sangeeta Bhaskar (2013). Nanoparticle mediated co-delivery of Paclitaxel and a TLR-4 agonist leads to tumor regression and enhanced immune response in the tumor microenvironment of mice. Int. J. of Pharmaceutics 445:171-180.
- Ankan Gupta, F.J. Ahmad, U.D. Gupta, M.Natarajan, V.M. Katoch & Sangeeta Bhaskar (2012) Protective efficacy of Mycobacterium indicus pranii against tuberculosis and underlying local lung immune responses in guinea pig model. Vaccine 30 : 6198-6209.
- Aniruddha Roy, S.Chandra, Swapna, Pramod Upadhyay & Sangeeta Bhaskar (2012) Anticancer and immunostimulatory activity by conjugate of paclitaxel and non-toxic derivative of LPS for combined chemo-immunotherapy. Pharm Res. 29: 2294-309.
- Ankan Gupta, F.J. Ahmad,U.D. Gupta, M. Natarajan, V.M. Katoch. & Sangeeta Bhaskar. (2012) Efficacy of Mycobacterium indicus pranii immunotherapy as an adjunct to chemotherapy for tuberculosis and underlying immune responses in the lung. PLoS ONE 7, e39215.
- Faiz Ahmad , Jiju Mani, Pawan Kumar, Seenu, Pramod Upadhyay, Sangeeta Bhaskar (2011) Activation of anti-tumor immune response and reduction of regulatory T cells with Mycobacterium indicus pranii (MIP) therapy in tumor bearing mice. PloS ONE 6, e25424.
- Aniruddha Roy, Manu Smriti, Pramod Upadhyay, and Sangeeta Bhaskar (2010) Combined chemo-immunotherapy as a prospective strategy to combat cancer: A nanoparticle based approach. Mol. Pharmaceutics 7: 1778–1788.
- Ankan Gupta, Nishamol, Jiju Mani, P.K.Upadhyay, V.M. Katoch, M. Natrajan, U.D. Gupta, Sangeeta Bhaskar(2009)Immunogenicity and protective efficacy of M.w against M.tb in mice immunized with live versus heat-killed M.w by the aerosol or parenteral route. Infection and Immunity 77:223-231.
- Pramod Upadhyay, Mahmud Hanif, Sangeeta Bhaskar (2006) Visual detection of IS6110 gene of M. tuberculosis in sputum samples by a test based on colloidal gold and latex beads. Clinical Microbiology and Infection 12: 1118 - 1122.
- Sangeeta Bhaskar* J.N. Banavaliker & Mahmud Hanif (2003) Large scale validation of latex agglutination test for diagnosis of tuberculosis. FEMSIM 1613 : 1-5.
- Sangeeta Bhaskar & Pramod Upadhyay (2003) Design and evaluation of an aerosol infection chamber for small animals. Int. J. of Pharmaceutics 255 : 43-48.
- Sangeeta Bhaskar, S.P. Khanna, Rama Mukherjee (2001) Isolation, purification and immunological characterization of novel low molecular weight protein antigen CFP 6 from culture filtrate of M.tuberculosis. Vaccine 18 : 2856-2866.