Benjamin C. Creelan, MD, an associate member of the department of thoracic oncology at Moffitt Cancer Center, is working to build on successes with tumor-infiltrating lymphocytes (TIL) in melanoma to create a viable therapeutic option for people with lung cancer who have experienced disease progression, regardless of PD-L1 expression level or genetic driver.
Dr. Creelan and colleagues conducted a single-arm open-label phase I trial using TIL plus nivolumab for 20 patients with advanced NSCLC who had experienced disease progression on or after nivolumab monotherapy. All patients underwent lymphodepletion followed by TIL infusion and interleukin-2 (IL-2). There was a prespecified severe-toxicity rate of < 17%, which was met, and there were three confirmed responses, two of which were ongoing at 1.5 years of follow up. In addition, there was a reduction in tumor burden for 11 patients, with the best median change of 35%.1
Dr. Creelan spoke with ILCN about his research and other ongoing work in the field, as well as about the pros and cons of TIL therapy for various patients.
ILCN: What clinical features of patients would make you reluctant to recommend this therapy?
Dr. Creelan: In this current form, this is an intensive treatment. This requires the patient to undergo both chemotherapy and IL-2. In patients with significantly impaired cardiopulmonary status, I would be careful before administering the current full dose lymphodepletion and IL2 regimen. Specific examples would be patients who require supplemental continuous oxygen or who have a recent history of acute cardiovascular events such as stroke or heart attack. This type of combination therapy is a physiologic stress for patients, so patient selection is important.
ILCN: What have been the challenges in moving TIL research forward?
Dr. Creelan: I think the main challenges are around lymphodepletion and IL2—particularly for patients who have received extensive prior therapy and are frail or infirm at presentation. We know that new bone marrow space must be made for the new T cells that are infused during TIL therapy, which is why we perform lympho-depletion chemotherapy prior to TIL therapy. Nonetheless, this process causes prolonged cytopenias for patients, which poses challenges for a short-term 2- to 4-week period. Another challenge is the surgery itself, which requires careful coordination and interdisciplinary review with a surgeon.
In addition, there is controversy about the role of post-TIL IL-2, and how much is truly required. It ‘stacks up’ in side effects for patients with pre-existing lung problems, like COPD or CHF. In general, it has been well-tolerated in patients who are never or light former smokers. Some trials that are currently under way or upcoming are using pegylated IL-2 versions, which may be less toxic than conventional IL-2.
Nonetheless, it will be a while before we see any results from these studies. The bottom line is that higher doses of IL2 are preferred, but the verdict is still out about whether this can be abbreviated or replaced.
ILCN: What has been your success with reinfusing TIL after a patient’s cancer progresses?
Dr. Creelan: I do not have personal familiarity with this. I haven’t heard of any “retreatment” case outcomes, apart from the famous case that was published in New England Journal of Medicine by Dr. Eric Tran.2 Dr. Tran and colleagues used a special selection method on the cells the second time around for a patient with colon cancer who had disease progression 6 months after their initial cell therapy, and the patient went into complete remission.
Because the cell selection process can take time, disease progression can be difficult to treat with TIL in the confines of a pre-existing clinical trial because it requires obtaining and selecting the new cells. We did have a patient with disease progression on our trial who we felt would be a good candidate because he had KRAS-specific T cells and an initial response. We could tell that his T cells were missing in his progressive tumor, so the cells just did not persist in his specific case. Unfortunately, his disease progressed substantially over the course of 3 months, and we were not able to perform the necessary steps in that time.
I find that patients with KRAS mutations tend to have aggressive, progressive, resistant, and refractory lung cancer. Unfortunately, there are very few trials for some KRAS subtypes. Within our trial, we are looking to potentially create a T-cell receptor (TCR) trial using the recombinant TCR from the patient I just mentioned—using an actual gene sequence from his T cell—so that we can potentially treat other patients with the same mutation going forward.
ILCN: Where are the successes with TIL therapy? What are the surprises?
Dr. Creelan: For our trial overall, I think the biggest success was that we did have some patients whose T cells recognized their unique tumor neoantigens, and those T cells did persist and have resulted in durable responses for a subset of patients.
I think the surprising thing was that the patients with low PD-L1 expression seemed to respond to this, and we’ve classically thought of PD-L1 zero or low as being less likely to respond to immune therapy. There is also promise for patients who have never chosen to smoke—patients who, again, really don’t classically or commonly respond to immune checkpoint inhibitors—because it’s still possible for their T cells to recognize their unique cancer mutations.
Regarding data beyond our trial, Schoenfeld et al. data3 were presented at the SITC meeting in November 2021. Those data show that patients on the trial experienced durable responses despite being heavily pretreated (> 2 prior lines of systemic therapy) and regardless of PD-L1 expression. Of the 28 evaluable patients the overall response rate was 21.4% (n = 6), and the median duration of response was not reached. Of the six patients with response, 83% were still demonstrating response at the last follow up (median study follow up, 8.2 months). Interestingly, one patient had a complete metabolic response that was found to be ongoing at 20.7 months of follow up. Two of the six patients with demonstrated response were PD-L1 negative.
So, to compare our trial with theirs, about 50% of patients on our trial were treatment naïve, and we harvested the tumor from PD-1 naïve tumors. The patients had not received an anti-PD-1 antibody at the time of enrollment. If the patients’ tumors were growing or they were developing new lesions on PD1 antibody, we treated them with a TIL. However, the actual TIL came from a PD-1–naïve tumor, whereas, in the Schoenfeld study, those tumors were resected from patients who had experienced disease progression after two, three, or four lines of treatment.
In the recent Iovance trial, it was aiming for a higher bar—more relapsed and refractory disease—and the T cells themselves probably had been through a lot more prior treatment as well.4 This may matter because we believe that as patients receive a PD-1 antibody, their T cells do get exhausted eventually.
It is like a race. We’re the jockey, and we’re trying to get that horse—the T cell—to the finish line. The longer we spur that horse onward, eventually it’s going to tire out. So, T cells in patients who have undergone multiple lines of therapy have been spurred for maybe 6 to 24 months, and then they’re resected and used for TIL. I am interested to see how long T cells can endure.
ILCN: Are there predictive biomarkers associated with TIL?
Dr. Creelan: No, we don’t really have a sense of that yet. If the patient’s TIL recognizes their unique cancer mutations, that seems likely predictive for benefit, but that’s a very retrospective marker. In that case, you’ve already harvested the TIL, and you’ve already done a lot of background research to uncover this. But upfront, de novo factors such as age, mutation burden, PD-L1, and smoking history don’t seem to really correlate in our small, limited datasets so far.
ILCN: How comfortable are you recommending this therapy for patients with driver-mutated lung cancer?
Dr. Creelan: I think that this is a strong research option for those patients who have experienced disease progression on or after conventional tyrosine kinase inhibitors or other targeted therapies. We know that resistance is inevitable, unfortunately, so there are probably more proteins or mutations for your immune system to target in that context. In addition, patients with relapsed or refractory receptor-tyrosine kinase driven lung cancer tend to be motivated regarding trying treatments that could extend their lives beyond more than mere months.
Unfortunately, conventional chemotherapy / immune checkpoint inhibitors are going to buy them months, but not years. Cell therapy using TIL could potentially be effective for years—a long duration of response is a hallmark of TIL, as showcased in melanoma. So that’s the attractive feature of it for those patients.
ILCN: Is this therapy cost prohibitive in the real world?
Dr. Creelan: This is an elaborate procedure, with a number of associated costs from growing the cells to maintaining sterility of the clean room. There is a limited pool of immunology technicians trained for this type of work, so there is extremely competitive demand. The supplies alone are quite expensive since everything must meet strict U.S. FDA or European Medicines Agency manufacturing guidelines. This all results in an absolute cost of this therapy of at least $100,000.
So, if it comes to market, this will be an expensive therapy, much like Yescarta or Kymriah, which of course will be a barrier for disadvantaged patients worldwide. Nonetheless, it’s impossible to put a ‘dollar value’ on enjoying an enduring response for patients living high-quality normal lives using a one-time treatment.
One thing that could perhaps decrease cost is the elimination of duplication of effort regarding the various standard operating procedures for each cell therapy facility. There are some universally accepted guidelines, but everyone uses different machines and different reagents, which is inefficient. At SITC, we have a cell therapy task force that is looking to improve this and make guidelines more transparent.
It’s important to note that some lung cancer specialists still hold a nihilistic view, adopted in the 1980s and 1990’s about doing as little as possible for lung cancer, since it is an incurable illness. These people often view any cell therapy as cumbersome, logistically challenging, or irrelevant to those patients who are already very ill.
Still, we are just in our infancy with this research, and these are expected hurdles. We are working to find ways to better optimize these therapies so that they will be more broadly applicable and cost effective.
For more on this topic, listen to this interview with Dr. Creelan and Dr. Prasad Adusumilli on IALSC’s podcast Lung Cancer Considered.
- 1. Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Med. 2021;27;1410-1418.
- 2. Tran E, Robbins PF, Lu Y-C, et al. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016; 375:2255-2262.
- 3. Schoenfeld A, Lee S, Paz-Ares L, et al. 458 First phase 2 results of autologous tumor-infiltrating lymphocyte (TIL; LN-145) monotherapy in patients with advanced, immune checkpoint inhibitor-treated, non-small cell lung cancer (NSCLC). Journal for ImmunoTherapy of Cancer. 2021;9:doi: 10.1136/jitc-2021-SITC2021.458.
- 4. First phase 2 results of autologous tumor-infiltrating lymphocyte (TIL; LN-145) monotherapy in patients with advanced, immune checkpoint inhibitor-treated, non-small cell lung cancer (NSCLC).