Helping the Immune System Beat Cancer: Biologics in Immuno-oncology Research

Cancer is not a singular disease, but a blanket term referring to an observed end-effect – the deleterious presence of abnormal cell growth within the human body – that can result from an almost infinite number of pathogenic mutations, mechanisms, and phenomena. Although individual cancers can and do share common traits (e.g., locations, cell types, biomarkers), each patient’s cancer is in effect a different disease. This heterogeneity has made cancer one of the most difficult diseases to control and treat, as limitations in terms of knowledge, technology, and logistics have historically made individualized therapeutic options unfeasible and forced scientists and clinicians to mostly focus on brute-force approaches such as radio- and chemotherapy. 

Under optimal circumstances, oncogenic cells are detected and eliminated by the body’s own immune system. As such, scientists have been seeking ways to harness and augment the body’s innate protective mechanisms to combat cancer in a more targeted manner. While researchers have investigated the potential of restricting cancer cell growth by manipulating growth factor production1 and angiogenesis,2 the majority of research has focused on modulating immune mechanisms using biologic agents, giving rise to the field of immuno-oncology.

Immuno-oncology requires a multi-pronged approach

Immuno-oncology seeks to characterize immune-cancer cell interactions under both physiological and pathological conditions, striving to identify the circumstances that allow cancer cells to escape and thrive. This involves a myriad of factors and parameters (e.g., phenotype, signaling, environment) interacting in a fluid and complex manner, so it is not surprising that a diverse range of biological agents have been, and are currently being developed for immuno-oncology research.

Antibodies are integral to immune signaling, mediating such critical mechanisms as effector cell activation, targeting selectivity, and long-term memory. The inherent malleability of the antibody has also made it a prime candidate for research and therapeutic use, as researchers are now able to produce large quantities of antibodies primed against any antigen they wish. Antibodies have been developed as checkpoint inhibitors, agents that prevent immune cells from interacting with shutdown proteins (e.g., CTLA-4, PD-1) expressed by cancer cells.3 They have also been used as agonists to activate immune cells or stimulate their function, and to directly target antigens expressed by tumor cells, thereby marking them T cell-mediated cytotoxic cell death.3,4

While antibodies mark targets and direct traffic, immune cells are required to actually eliminate cancer cells. Adoptive cell therapy research aims to devise methods to increase the efficacy of the body’s own cytotoxic T cells, whether by increasing their number, stimulating their activity, or enhancing their targeting capabilities. They can accomplish this by a number of in vitro techniques, including clonal selection and expansion and genetic engineering. CAR-T cells, which possess artificially constructed T-cell receptors (TCRs) capable of bypassing TCR-mediated mechanisms of immune evasion, are perhaps the most famous product of adoptive cell therapy research. 

It is now well understood that cancer cells also act in a paracrine manner to promote an anti-inflammatory microenvironment designed to suppress immune function. Potential therapeutic avenues utilizing pro-inflammatory cytokines and chemokines (e.g., interferons, interleukins) have been investigated, with the goal of stimulating immune cell function and/or promoting pro-inflammatory cell phenotypes.

A vaccine against cancer?

Preventative anticancer vaccines have been successfully developed for situations where the causative agent is known, such as hepatitis B virus-mediated liver cancer and human papillomavirus-mediated cervical cancer.4 Research is still ongoing regarding the prospect of a therapeutic vaccine – where the immune system is trained to recognize, memorize, and attack cells expressing cancer cell-specific antigens. Various inoculation approaches have been attempted, including the use of peptide antigens, viral vectors carrying recombinant proteins, and even extracted dendritic cells which are treated with antigen in vitro and then reintroduced.4 To date, efficacy has been relatively limited, as even cells programmed to detect and eliminate tumor cells can be suppressed in other manners (e.g., environmental cytokine signaling, interactions with anti-inflammatory cells).4

An individual solution to an individual disease

Immuno-oncology researchers work to not only locate potential therapeutic targets, but also develop the technology and logistics to rapidly and accurately identify the unique oncogenic markers specific to each individual. Their endeavors in this latter area have been greatly aided by recent developments in next-generation sequencing techniques which have improved sequencing depth, accuracy, and throughput.5 The stage is therefore being set for the eventual development of individualized cancer diagnoses and therapeutics.

References:
  1. E. Witsch et al., “Roles for growth factors in cancer progression,” Physiology (Bethesda), 25(2):85-101, 2010.
  2. N. Nishida et al., “Angiogenesis in cancer,” Vasc Health Risk Manag, 2(3): 213-219, 2006.
  3. A.M. Scott et al., “Monoclonal antibodies in cancer therapy,” Cancer Immun, 12:14, 2012.
  4. I. Mellman et al., “Cancer immunotherapy comes of age,” Nature, 480(7378):480-489, 2011.
  5. K. Kakimi et al., “Advances in personalized cancer immunotherapy,” Breast Cancer, 24(1):16-24, 2017. 
 

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