Immunology and Biotherapies

Opinion from JAMA Oncology — Enlisting the Immune System to Cure Breast Cancer—A Recipe for Success

Tumor-infiltrating lymphocytes (TILs) reflect the strength of an individual patient’s antitumor immune response, with most cells representing a T-cell infiltrate, typically of activated memory phenotype.3Indicative of the degree of an endogenous antitumor response, it is likely that TIL-rich and TIL-poor breast cancers exhibit markedly different responses to therapy, and while unable to reject a clinically detectable tumor at the primary site, the generation of immunological memory has the potential to effectively control residual disease, thereby improving long-term outcomes. Adjuvant cytotoxic treatments, such as chemotherapy, may jumpstart this process by inducing a broader range of antigen-specific immune responses. These hypotheses are supported by studies4- 6 showing that the degree of lymphocyte infiltration is predictive of a better local response to neoadjuvant treatments in triple negative and HER2-positive cancers. For instance, in the NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization, which evaluated single and dual anti-HER2 blockade followed by taxane- and anthracycline-containing chemotherapy), higher levels of TILs were found to be prognostic in all anti-HER2 therapy arms and were associated with increased pathologic complete response rates as well as improved event-free survival.6

Adjuvant poly(N-isopropylacrylamide) generates more efficient monoclonal antibodies against ... http://t.co/HAtCVrK52x #biotech #science

Abstract

Adjuvants play an important role in eliciting immune responses and subsequent generation of antibodies with high specificity. Recently, poly(N-isopropylacrylamide) (PNiPAAm), also known as a “smart” polymer, has been proposed as a potential adjuvant for making antibodies and vaccines. This material exhibits efficient delivery, protection against degradation, and preservation of antigen epitopes. In this work, we used both CFA and smart polymer to develop a highly specific murine monoclonal antibody (mAb) against recombinant truncated histidine rich protein2 (HRP2) of P.falciparum. Our results indicate that the mAbs developed using these adjuvants were able to recognize recombinant HRP2 and native PfHRP2 protein from spent medium. The mAbs generated against recombinant truncated HRP2 showed better sensitivity to the antigen and importantly mAbs generated through PNiPAAm adjuvant were in the range of 108 to 109 M-1. The mAbs generated through PNiPAAm are very efficient and sensitive in detecting HRP2. To the best of our knowledge, this is the first report of such comparison having been made between these two adjuvants and we propose that the smart polymer has huge potential as an alternative to CFA. Additionally, we discuss the utility of the mAbs generated through PNiPAAm for specific diagnosis of malaria caused by P.falciparum.

Abstract

Keywords: 

Vaccine; Immunotherapeutic; Cancer; Clinical trial

Fig. 1. Summary of immunotherapeutic vaccine trials registered since 1999 to 2014. A, Total number of immunotherapeutic anti-cancer phase 2, phase 2 & 3 and phase 3 trials in dataset collected on 27th October 2014. B, Breakdown of the vaccine categories under investigation. Values above or below the arrow indicate the ratio of trials in Phase 3: Phase 2 for the vaccine category (# phase 3 trials/# phase 3 trials *100). C, Comparison of vaccine categories examined in trials completed between 1999–2013 and in 2014 onwards. D, Frequency of the most used adjuvants in vaccine trials completed between 1999–2013 and in 2014 onwards

Chemotherapy and/or radiation therapy are widely used as cancer treatments, but the antitumor effects they produce can be enhanced when combined with immunotherapies. Chemotherapy kills tumor cells, but it also releases tumor antigen and allows the cross-presentation of the tumor antigen to trigger antigen-specific cell-mediated immune responses. Promoting CD4+ T helper cell immune responses can be used to enhance the cross-presentation of the tumor antigen following chemotherapy. The pan HLA-DR binding epitope (PADRE peptide) is capable of generating antigen-specific CD4+ T cells that bind various MHC class II molecules with high affinity and has been widely used in conjunction with vaccines to improve their potency by enhancing CD4+ T cell responses. Here, we investigated whether intratumoral injection of PADRE and the adjuvant CpG into HPV16 E7-expressing TC-1 tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and PADRE was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and PADRE also enhanced the generation of PADRE-specific CD4+ T cells and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci. The treatment regimen presented here represents a universal approach to cancer control.