Clinical Perspectives

Thoracic Immunotherapy Trial Portfolio: Advancing T-cell Immunotherapies to the Next Generation

December 11, 2015

Thoracic-Immunotherapy-Trial-Portfolio Photo Courtesy of Bristol-Myers Squibb Company.jpg

Ben Creelan, MD, MS

The advent of immunotherapy is revolutionizing the treatment of lung cancer. It has changed our conversation with patients, and above all, their expectations. Particularly attractive are the minimal side effects of immunotherapies and the potential for a durable remission. 

Still, I'll be honest. Commercial PD-1 inhibitor (PD1i) monotherapy such as Opdivo or Keytruda works in too few patients, and still leaves the majority with progressive disease. The use of tumor biomarkers such as PD-L1 immunohistochemistry for predicting responders remains fraught with problems. At best, it is a crude surrogate that neither weeds out non-responders, nor guarantees a good response. Even using the highest cutpoints for PD-L1+, the objective response rates remain less than 50%.

Adoptive cell transfer using TCR technology (Reference: Fujiwara H. Pharmaceuticals 2014, 7(12), 1049-1068)
Adoptive cell transfer using TCR technology (Reference: Fujiwara H. Pharmaceuticals 2014, 7(12), 1049-1068)

These problems have resulted in an unmet need for more effective ways to stimulate effector T-cells. At Moffitt, the Thoracic Oncology team is tailoring our trial portfolio to address PD1i relapsed patients. We realize your patients may travel a long way to reach us, so our portfolio emphasizes phase I/II trials, in which eligible patients are guaranteed to receive the experimental agent. We also try to avoid trials with protracted screening periods, so patients are not hanging in limbo for many weeks. 

  • CTLA4i plus anti-PD(L)1i - This concept has resulted in clear synergy in melanoma, as evidenced by the Checkmate 066 trial. We are extending this concept into lung cancer.
  • Adoptive cell transfer using TCR technology - Similar to CAR-T cell therapy, genetically modified T-cell receptors (TCRs) directly bind to a target antigen presented by Class I. The advantage of TCR over CAR-T is that intracellular proteins can be targeted, permitting more intelligence in the choice of tumor antigen. Response rates exceeding 50% have been reported in synovial sarcoma. We currently have two trials for non-small cell lung cancer opening. These use genetically modified TCR targeting either NY-ESO1 or MAGE-A10. In order to be eligible, the patients must have excellent organ function. In addition, their tumors must be centrally tested to confirm if they express the target antigen. Eligible patients undergo leukapheresis at our center and their T-cells are transduced with a viral vector at an outside facility. They then receive conditioning chemotherapy followed by inpatient admission for T-cell infusion. These patients are cared for by a new integrated inpatient/outpatient team where they are monitored for cytokine release syndrome. 
  • Adenosine A2A receptor inhibitors - We believe other immune checkpoints are also important to target. Tumors can co-opt T-cell regulation in the extracellular environment and create tolerance via the adenosine 2-deaminase (A2AR) receptor. This phenomena called the Warburg effect. Inhibition of A2AR shows promising results in human tumor xenografts. Thus our center is enrolling a trial with the first A2AR antagonist. 

Outpatient Continuity of Care 

Our Direct Referral Center (813-745-1831) is an urgent care clinic which is open 24 hours a day, 7 days a week. It is expanding to up to 24 beds to accommodate increased demand. Moreover, we can also coordinate direct admissions for established patients. Our goal is that patients screening or receiving treatment on clinical trials will receive continuous care and always have an accessible route for evaluation and treatment. We believe oncologists in busy practices should not be burdened with managing complications from our trials. We will do our utmost to ensure that patients have access during off-hours. 

Where to Start?

The best way to begin is to refer the patient for a new appointment to be seen by a medical oncologist at Moffitt. We have seven medical oncologists dedicated to thoracic cancers. Our standard is to optimally have all patient referrals seen within a week. This shows the patient is interested, facilitates communication, and allows us to assess eligibility in real-time.

It's Never Too Early to Refer

Although many of our trials only accept patients with relapsed cancer, I encourage the referral of patients before relapse or progression occurs. Particularly for small cell lung cancer, patients sometimes decline to an ineligible state by the time they reach the cancer center for a clinical trial referral. Like football, it is easier to throw a pass before the defensive end is a yard away. An early visit can help outline expectations and empower the patient for when relapse occurs.