Oncology Treatments: From novel Diagnostic Tests to Targeted Therapy and Immune-checkpoint Blockade Therapy

By Dr. Maria Benito

Cancer is defined as malignant overgrowth of abnormal cells which tend to proliferate in an uncontrolled fashion, spread from the original site, invade, and metastasize nearby tissues. Giving the importance of an early diagnosis for the positive outcome, efforts has been focused not only in developing new and more effective treatments, but also in learning more about the pathogenesis of different type of cancers and main players involved, and improving the diagnostic techniques.

Proteins, biomarkers, DNA and biopsies are used in cancer diagnostic. Novel, faster, more effective and less invasive tests are continuously being studied and developed. In this regard, pharmaceutical companies –in collaboration with universities in most cases– are embedded in the development of new diagnostic test.

Scientists in the University of Leeds have been conducting research into developing a treatment for head and neck cancers that could reduce the need for traditional radio and chemotherapy programmes using robotics, nanoparticles, ultrasound and lasers that create metallic particles that are attached to cancerous cells and exposed to laser and ultrasound illumination.

Biopsies can be traumatic and painful; research has been widely performed into non-invasive alternatives. Recently, scientists from the Johns Hopkins Kimmel Cancer Centre has developed CancerSEEK, a single blood test which screens for eight common cancer types –ovary, liver, stomach, pancreas, oesophagus, colorectum lung or breast– and helps identify the location through various biomarkers. This test will enhance cancer screening in a cost-effective manner in the future. In Japan, Hitachi in collaboration with Nagoya University are developing a test to detect breast and colon cancer –a prominent type of cancer difficult to detect early and with a high incidence in Japan– using urine samples. These non-invasive procedures that will allow detecting cancers in a very early stage are expected to become available in 2020.

Vitravki® (larotrectinib) developed by Bayern has also been approved by the FDA as a biomarker-based cancer treatment for adult and paediatric patients with solid tumours that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation.

Although the early diagnosis is the best chance for a positive outcome, the treatment and management of cancer are critical. Local control of the tumour with surgery –which means the total eradication of the primary tumour and disease– is generally the best option to achieve cure.

Using tight beams to defined areas in the body, radiation treatment –usually X- or gamma rays, given by electron beam accelerators or particle accelerators– allows for the treatment of tumours with minimal radiation being delivered to surrounding normal tissue, and can also attain remission in some type of malignancies.

Traditional chemotherapy had the downside of affecting cells in a non-discriminatory way because the cytotoxic agent can inhibit or kill any rapidly growing or developing cell –tumour or normal–, as it targets non-specific cells with highly toxic effects. Targeted therapies on the other hand, attack cellular proteins responsible for producing abnormal cell growth, while hormone therapy can be an effective treatment for cells with particular receptors that often behaves stimulating cell growth.

Other treatments include immunotherapy –based in the administration of antibodies or vaccines to stimulate the immune system to reject the cancer cells–, gene therapy, or immune-checkpoint blockade therapy. Studies continue searching for new and more effective cancer treatments, and there is a continuous improvement with novel experimental therapies.

Regulation of innate immune signalling and Immune-checkpoint blockade therapy 

Cancer cells are resistant to apoptosis, cell cycle arrest, and senescence. Targeted therapies inhibit tumour growth and progression by blocking mutant proteins and signalling pathways essential for cell survival. Tumours can also deregulate the immune system by altering checkpoints –the balance between activating and inhibitory signals– in different T cells regulatory pathways.

There are three potential immune profiles for tumours: (1) those that are infiltrated with T cells and express inflammatory genes, which could respond to checkpoint inhibition; (2) tumours without T-cell or inflammatory infiltrate that could react to adoptive cell therapy; (3) and tumours with immune cells –including T cells– at the periphery or in the stromal tissue but not within the tumour, which might respond to anti-angiogenic therapy.

The strategies for cancer immunotherapy involve the direct attack of the tumour, activation of the immune system cell therapies with stimulatory agonists or immune-checkpoint blockade, –such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death-1 (PD-1), which can decrease the tumour immunosuppression– or gene therapy, which allows modifying tumour gene expression for therapeutic purposes.

Innate immune activation –initiated with the recruitment of CD8+ T cells capable to kill tumoral cells– plays a critical role in the spontaneous adaptive immune response against cancer. The phenotype of infiltrated immune cells –inflammatory versus non-inflammatory– appears to have a key role in the resolution of the tumour. CD8+ T cells seem to evoke resistance to checkpoint blockade immunotherapy, and have been proposed as a prognostic biomarker, since inflammatory infiltrated cells correlate with positive treatment outcomes.

Other innate cell subsets may also influence the efficacy of immunotherapies in early phases of tumours. Macrophages and neutrophils attack tumour cells and stimulate cytotoxic T lymphocytes (CTL), antigen-presenting cell (APC) and natural killer (NK) cells, whilst inflammatory cells produce growth and angiogenic growth factors that promote tumour growth. NK cells have been described to contribute to tumour control in some cases, but also have been shown to cause immune suppression, partly through PD-L1 expression. Similarly, γδT cells are capable to recognize and kill tumour cells in some circumstances, but some γδT cells display a regulatory function too. NKT cells can be either anti-tumour or tumour-promoting.

Regulatory T (Treg) cells –key mediators of immunological self-tolerance– regulate immune responses and inflammation. Treg cells –which require T-cell receptor (TCR) stimulation– suppress immune response against self-antigens, but also anti-tumour immune response. Treg cells can suppress different immune cells such as T –CD4+ and CD8+– and B lymphocytes, dendritic cells (DC), NK, NKT cells, and monocytes/macrophages via humoral and cell-cell contact mechanisms through CTLA-4, IL-2, IL-10, TGF-β, IL-35, GITR, LAG3, granzyme B, adenosine, and cAMP. Thus, infiltration of a large number of Treg cells into tumour tissues is associated with poor prognosis.

Anti-cancer drugs, ionizing irradiation, or tumour antigen vaccination may cause local inflammation, which recruit and activate Treg cells in tumour tissues. Low doses of cyclophosphamide –used in traditional chemotherapy–, selectively reduce highly proliferative Treg cells in the tumour tissues, enhancing anti-tumour immune responses. Combination of Treg cell attenuation with the activation of tumour-specific effector T cells –by cancer vaccine or immune checkpoint blockades– may enhance each individual treatment and improve cancer immunotherapy.

Recent progress in cancer immunotherapy targeting Treg cells suggests that molecules relatively specific to Treg cells –CTLA-4, GITR, CCR4, PD-1, OX-40, and LAG3, CD25 and CD15s– are good candidates for Treg depletion or modulation.

One of the Latest breakthroughs in cancer immunotherapy is the clinical use of the checkpoint blockade therapy with monoclonal antibodies against CTLA-4 (Ipilimumab and Tremelimumab), constitutively expressed on Treg cells, and transiently expressed by T cells upon activation. It remains to be determined whether anti-PD-1 antibody (Nivolumab), another checkpoint blockade antibody, possesses a Treg-depleting effect in tumour tissues.

STING and Batf3 –implicated in anti-tumour T cell response and tumour control–, have been associated with the ability of responding to checkpoint blockade immunotherapy, although chronic activation of this pathway can also promote tumorigenesis.

Therefore, the failure of immune responses to eliminate the tumour may be due to suppressive mechanisms such as immunoregulatory cells recruitment, or upregulation of inhibitory pathways including receptors CTLA-4 and PD-1 checkpoints expressed on tumour-infiltrating lymphocytes (TILs).

Modern immunotherapy approaches have focused on boosting T cell responses and stimulating cell mediated immunity aiming for tumour destruction –known as immune checkpoint blockade– initiated with antibodies against CTLA-4 –ipilimumab and tremelimumab– and against the PD-1 T cell co-receptor –nivolumab and pembrolizumab– and its ligand B7-H1/PD-L1 –durvalumab, atezolizumab, avelumab.

CTLA-4 blockade –vital in T-cell activation– affects the intra-tumoral immune response inactivating Treg tumour-infiltrating lymphocytes; PD-1 –expressed in stimulated T cells, and in Treg lymphocytes, B-activated cells and NK cells– acts as immune-checkpoint and immune-therapeutic target.

Anti-CTLA-4 and anti-PD-1 anti-tumour responses are driven by distinct cellular mechanisms, and CTLA-4 and PD-1 attenuate T cell activation through different processes too. CTLA-4 is upregulated after binding TCR, and attenuates early T cell activation through cell intrinsic and extrinsic mechanism. PD-1 is induced later during T cell activation, and after binding PD-L1 or PD-L2, attenuates TCR signaling –therefore T cell activity– in peripheral tissues through cell intrinsic mechanisms.

Immune-checkpoint blockade therapy with ipilimumab, nivolumab, and pembrolizumab are currently being used in clinic. A combined therapy to block both pathways –CTLA-4 and PD-1– simultaneously are currently been studied.

Although the search for biomarkers that can predict benefit from the use of drugs and what patients would respond to them is vital in cancer immunotherapy, so far there is no useful biomarker associated with checkpoint blockade. The number of CD8+ T-cells infiltrating the tumour microenvironment and expressing PD-1 and/or CTLA-4 –whose blockade may increase the proportion of infiltrating T cells– seems to be a key indicator of positive outcome with checkpoint inhibition and the most reliable biomarker.

 

Abbreviations

APC: antigen-presenting cell

Batf3: Basic Leucine Zipper ATF-Like Transcription Factor 3

B7-H1: also named PDL-1 or CD 274

cAMP: 3′,5′-cyclic adenosine monophosphate

CCR4: CC chemokine receptor 4

CD15: cluster of differentiation 15 or Sialyl LewisX

CD25: α chain of the high-affinity IL-2 receptor

CTL: cytotoxic T lymphocytes

CTLA-4: cytotoxic T lymphocyte-associated antigen 4

DC: dendritic cells

GITR: glucocorticoid-induced TNF receptor

IL-2: interleukin-2

IL-10: interleukin-10

IL-35: interleukin-35

LAG3: lymphocyte-activation gene-3

NK: natural killer cells.

NKT: natural killer T cells

NTRK: neurotrophic receptor tyrosine kinase

OX-40: (CD134): members of the TNFR/TNF superfamily expressed on activated CD4 and CD8 T cells

PD-1: programmed death-1

PD-L1: programmed death-ligand 1

PD-L2: programmed death-ligand 2

STING: stimulator of interferon genes

TCR: T-cell receptor

TGF-β: transforming growth factor beta

TILs: tumour-infiltrating lymphocytes

TLR: Toll-like receptor

TNF: tumour necrosis factor

Treg: regulatory T

 

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