In patients with rare or underserved conditions, it can sometimes be difficult to receive effective treatment. For example, chemotherapy, the standard-of-care for Langerhans cell histiocytosis (LCH), is only effective in around 50% (or less) of cases. According to a news release from Baylor College of Medicine, shared on ScienceDaily, researchers are now looking to address this efficacy issue through combination therapy. In mice models of LCH, MAPK inhibitors, alongside PD-1 targeting immunotherapy, significantly reduced LCH disease burden. Check out the full study findings published in Blood.
The Research
Within this particular research, Dr. Rikhia Chakraborty had two goals:
- Identify some of the potential causes of LCH.
- Determine better, more effective, and more accessible therapeutic options.
The research showed that cytotoxic T cells (which kill foreign invaders) and regulatory T cells (which, as suggested, regulate the immune system) are both found on these lesions. But because the cytotoxic cells are in “exhaustion,” they are unable to combat lesion development. Normally, cellular exhaustion occurs after the body clears a viral infection. Finally, the T cells are able to relax, done fighting the foreign invaders. In patients with LCH, diseased cells use programmed cell death protein 1 (PD-1) receptors, which help turn “off” T cells, to manipulate T cells into entering exhaustion. Thus, researchers determined that PD-1 modulating therapies could be beneficial in combatting Langerhans cell histiocytosis.
PD-1 and MAPK
Next, researchers decided to use PD-1 modulating therapies alongside MAPK inhibitors to determine its efficacy. In the past, the MAPK pathway has been shown to play a role in LCH. MAPK inhibitors have even reduced related symptoms and lesions, though these results are not sustained. As a result, researchers questioned whether supplementing this treatment would be beneficial.
To evaluate this, the research team combined PD-1 targeting immunotherapy with MAPK inhibitors. Together, these both target disease-causing dendritic cells and stop T cells from exhaustion. Next, they evaluated this therapy in mice models of LCH. To do this, researchers evaluated both PD-1 targeting therapy and MAPK treatment alone, and then in conjunction. Findings show that:
- MAPK inhibitors alone reduced LCH cells but not T cells forming lesions. Alternately, anti-PD-1 therapy reduced T cells but not LCH cells.
- When using a combination of the two therapies, researchers saw a significant reduction in both cells.
Langerhans Cell Histiocytosis (LCH)
Although the exact cause of Langerhans cell histiocytosis (LCH) is unknown, many believe it could be caused by an unusual immune response or MAPK mutations. Additionally, smoking increases the risk of LCH. Altogether, LCH is a rare inflammatory disorder in which the body produces too many Langerhans cells (also known as histiocytes). Normally, these histiocytes, a type of white blood cell, play a role in immune response and protect the body from infections and foreign invaders. However, in LCH, an excess of Langerhans cells cause tumors (granulomas) to form throughout the body. Although LCH more often affects children, it can affect older adults as well. Symptoms vary based on what part of the body is affected (ex: skin, bones, liver, spleen). However, some potentially observable symptoms include:
- Swollen lymph nodes
- Jaundice (yellowing of the skin and eyes)
- Red, scaly papule on the skin
- Bone pain, swelling, or fracturing
- Prolonged clotting time in the liver
- Bulging eyes
- Delayed or absent puberty
- Infertility
- Thyroid dysfunction
- Irritability
- Difficulty breathing
- Excessive urine production
- Dizziness
- Seizures
