The Role of Targeted Agents and Their Effects on Lymphocytes and Patient Outcomes

The relationship between the immune system and cancer has been of interest to the scientific community for decades. In 1909, Erlich suggested that the immune system plays a critical role in suppressing tumor cell development, termed immunosurveillance. The lymphocyte serves an important role in this process by recognizing non-self cells and mediating cell killing through complex mechanisms. Lymphocytes that infiltrate tumors are known as tumor infiltrating lymphocytes (or TILs) and have also been linked to a more favorable predictor of survival for many tumor types including colorectal cancer, breast cancer, esophageal cancer, ovarian cancer, cervical cancer, and oral squamous cancers. On the other hand, cancer cells have developed an innate ability to escape the immune system targeting foreign cells for destruction by down regulating key players including lymphocytes. Naturally, impairment of host immunity is associated with worse outcomes.

Prior studies have shown that a low lymphocyte count at diagnosis or prior to treatment is linked to a lower overall survival regardless of treatment. Fogar looked at patients with pancreas and biliary tract tumors and found that patients with cancer had lower levels of circulating lymphocytes compared to healthy controls. Patients with less than 1.2 x 109/L circulating lymphocytes had shorter survival than those with values greater than 1.2 x 109/L (p<0.01). Another study showed that pancreas cancer patients with a lower neutrophil to lymphocyte ratio (NLR) had a median overall survival of 2.4 months compared to 7.7 months in patients with a normal NLR. A lower lymphocyte count has been associated with shorter survival times in patients with various other solid tumors including colorectal, non-small cell lung cancer, and ovarian cancer.

Patients with low lymphocyte counts after treatment have also been shown to have shorter survival times. Campian and colleagues looked at patients with stage III non-small cell lung cancer. Eighty- nine percent of patients had normal total lymphocyte counts (defined as > 1,000 cells/mm3) prior to receiving standard therapy. Two months after starting treatment, a 67% overall reduction of total lymphocyte counts was seen, with a median of 500 cells/mm3. This occurred irrespective of the chemotherapy regimen given. Analysis showed a 70% higher rate of death related to lower total lymphocyte counts at 2 months compared with those with a count higher than 500 cells/mm3.

To date, no study has evaluated the role of targeted agents in different tumor types and their effect on lymphocyte numbers and outcomes. The purpose of our study will be to evaluate targeted agents as a single agent to determine if 1) there is a relationship with circulating lymphocytes and 2) if low lymphocyte counts related to treatment can be associated with outcome.