Tumor-Infiltrating Lymphocytes: Rationale for Use in the Treatment of Solid Tumors and Potential Benefits and Drawbacks

Tumor-infiltrating lymphocyte (TIL) therapy is an adoptive cellular therapy in which infiltrated lymphocytes are harvested directly from a patient’s tumor and grown in large numbers in vitro. TILs can recognize many targets on cancer cells, including unique targets. The TILs are genetically engineered to better attack tumor cells before being reintroduced to the patient through infusion to aid the immune system. This form of immunotherapy is under investigation in several clinical trials.

Targeted Oncology™: What have you learned about tumor-infiltrating lymphocytes in melanoma?

Ben Creelan, MD: I was fortunate to go to ESMO [European Society for Medical Oncology Congress 2022] this year where John Haanen [MD, PhD] was presenting data from a randomized open-label phase 3 trial, where metastatic melanoma patients who had progressed on previous anti–PD-1 therapy were randomized to either our gold standard since 2011, ipilimumab [Yervoy], given at a standard dose every 3 weeks for 4 doses, or TIL cell therapy. It was quite surprising to me that there was a significant difference in progression-free survival and a trend in overall survival between the 2 groups. I think that, historically, we’ve always viewed second-line ipilimumab to be the gold standard for patients with metastatic melanoma. I remember when it beat dacarbazine in 2011. Now I see TIL beating ipilimumab, and I see a real succession here. This is the first time that we have any randomized data with TIL therapy in any cancer. It's quite vindicating. It's especially reassuring to know that this is holding up in a robust fashion in patients who are refractory to previous anti–PD-1 therapy.

Targeted Oncology™: What is the rationale for use of TILs in advanced non-small cell lung cancer?

Ben Creelan, MD: The truth is, our second- and third-line therapy for advanced non-small cell lung cancer patients is lousy. You’re talking about progression-free survival of 4 or 5 months and response rates of less than 25% for the majority of patients, and a very toxic treatment, docetaxel, in this situation. Having something that actually allows us to aim for the fences rather than an infield bunt, or just striking out, is really exciting. TIL has the option for a durable response. As we saw from the Haanen data in melanoma, there’s a proportion of patients in that survival curve who are plateauing, going out past a year. That’s a similar trend that we’ve been seeing in lung cancer as well. I think this opportunity to go after a high-risk, high-reward type of a treatment is going to appeal to a lot of clinicians and patients. At the end of the day, that’s exciting, because historically, nothing’s really beaten that gold standard of docetaxel, which has been around since 1999.

Targeted Oncology™: What are the potential benefits and drawbacks of using TILs versus chemotherapy in patients with advanced non-small cell lung cancer?

Ben Creelan, MD: No doubt one of the biggest benefits is that you’re using a cell product that’s from that individual patient. It’s a very personalized type of treatment, the most personalized treatment we can give in cancer. Of course, there are drawbacks to that. Interleukin-2 [IL-2], TIL, and chemotherapy treatment can cause prolonged cytopenias that can last for a week or 2 weeks. The cytokine storm that happens with IL-2 treatment after TIL infusion causes fevers and rigors that can last for hours to days. The other factor is the capillary leak syndrome that happens with IL-2 treatment. We believe that IL-2 is important to help maintain the growth of the T cells once they [are infused]. However, it does come with a price, which is that it causes this leak of fluid between compartments of the body, which does make many patients retain fluid. It can cause shortness of breath, which requires oxygen for a period of time. But again, these toxicities all happen within the first week or so. I think if we can be attentive to them during that period, then patients usually can make it through fine. A really good analogy is the CRS [cytokine release syndrome] that happens with anti-CD19 CAR [chimeric antigen receptor] T-cell [treatment]. Originally, these [toxicities] were considered to be a deal-breaker, and yet we now have a situation where this is routine. The fact that we have standard operating procedures and staff trained to deal with these side effects has made CAR-T a very, very humdrum kind of treatment. We expect that with proper education, proper training, and management algorithms, TIL therapy will become the same way.

Targeted Oncology™: Can you provide an overview of the various TILs in development for advanced non-small cell lung cancer?

Ben Creelan, MD: There’s LN-145, which is the Iovance [Biotherapeutics] classic TIL product. [It] is the farthest along in its development pathway. There are 2 major trials exploring this. One in anti–PD-1 treatment-naïve non-small cell lung cancer, which is called COM-202. Data from that trial has not yet been reported. Although, data from other cohorts of that trial, such as melanoma, have been reported and show a very high response rate. I think that’s an exciting concept because we do think that TILs are even more robust and potent in the [anti-]PD-1 [treatment-naïve] patients or minimally exposed anti–PD-1 patients. There is also the LUN-202 trial, which is a phase 2 trial with a registration end point in the second-line non-small cell lung cancer space, after patients have progressed on previous anti–PD-1 axis therapy and chemotherapy. Both trials have the potential to be very impactful because 1 could garner approval for TIL in the second-line, non-small cell lung cancer space as an alternative to docetaxel, which, as I mentioned, is our historical gold standard. The previous trial has the option of [using] TIL as a combination with anti–PD-1 therapy. The next trial that I wanted to mention [uses] an interesting treatment strategy, which is knocking out the PD-1 receptor. Iovance has a follow-on trial using TIL in which the PD-1 receptor has been knocked out. The idea is that you can have more potent TIL that grow independently, which is what we find in animal models. We hope that [observation] would translate into patients, but that’s still in phase 1. The next trial that we have is [sponsored by] Instil Bio. This is called the phase 1/2 DELTA-2 trial, which is enrolling patients with non-small cell lung cancer who have progressed on previous chemotherapy and [anti-]PD-1 therapy. The interesting thing about that trial is that it allows patients with oncogene-driven non-small cell lung cancer, which is [a population that] the other trials did not [include]. Another interesting thing about that trial is that Instil Bio is harvesting tumors from patients and cryopreserving them, and then the TIL can be grown later from that tumor sample. That provides a bit more flexibility in the management and scheduling of [tumor harvesting] rather than having to set up an exact time where the tumor gets flown across the country on the same day as the surgery, or within a few days of the surgery, and then has to [be processed]. These tumor samples can simply be snap-frozen and then [TIL can be cultured and expanded later]. Of course, the downside to that strategy is that by cryopreserving the tumor without culturing any T cells or lymphocytes from it first, you may have less cell viability or a lower success rate. I await their data. In melanoma, they’ve certainly seen potent responses that seem quite comparable to the Iovance data that’s been historically presented. An even more-personalized treatment strategy is where we perform whole-exome sequencing of the patient’s tumor and select the T cells that recognize patient-specific mutations. This has been pioneered at the NCI with Steve Rosenberg and Jim Yang. They have case reports that this strategy can yield very durable responses in other disease types, although the totality of the data has not been presented in a clinical format to date. To my knowledge, the lung cancer results have not yet been presented in a public forum.

Targeted Oncology™: Can you discuss the TILs being developed for use in combination with checkpoint inhibitors for patients with non-small cell lung cancer?

Ben Creelan, MD: ITIL-168 has been studied as a monotherapy in melanoma, and the DELTA-2 trial is using it in combination with pembrolizumab [Keytruda], primarily for patients who have progressed on prior PD-1 inhibitor treatment. The rationale for that is without the addition of checkpoint blockade those TIL may become rapidly exhausted or inhibited by an unfavorable [tumor] microenvironment. The patient populations that the trial is enrolling are primarily lung cancer, head and neck cancer, and renal cell carcinoma. That’s an important consideration. There is also a strategy that Instil is using [for ITIL-306], in which they [add a] costimulatory antigen receptor (CoStAR). This gene modification of the TIL allows it to be more independent of exogenous cytokines. Preclinically, we find that those TIL tend to grow independently of IL-2, which is quite fascinating, and suggests that IL-2 won’t be required in that type of TIL.

Targeted Oncology™: Do recent data tell you anything about whether it might be more effective to give TILs in combination with an anti–PD-1 therapy for patients with advanced non-small cell lung cancer, or might you wait until after disease progression to use the therapy?

Ben Creelan, MD: There were some interesting data presented by Dr Christian Heinrichs, which indicated that whether 1 gives TIL al1 or in combination with a PD-1 inhibitor, the 2 treatments don’t necessarily seem to be synergistic. However, those are preclinical data. When one compares [data from] the Iovance COM-202 [trial] from patients with non-small cell lung cancer who had progressed after 2 to 3 prior lines of therapy, the response rates were around 21%, and not as durable as we would like. Whereas [when TILs are used] in combination with a PD-1 inhibitor, we’ve been seeing a [stronger] signal. It may have a lot to do with the type of TIL that are being resected from the patients’ [tumors]. There’s been this trend that the longer a patient has been exposed to a PD-1 or PD-L1 inhibitor, the less robust, the less naïve, or memory phenotype those TILs are. Waiting until disease progression is not the best time to be treating these patients with TIL. If we think about allogeneic transplant, we don’t transplant patients when they have 50,000 blasts in their peripheral blood. That’s too much for the immune system to take care of. I think that’s very true with adoptive cell therapy as well, that the best time to give it is probably when you have less burden of disease and you have more of a chance for the immune system to eradicate those residual cl1s of tumor.

Targeted Oncology™: In your practice, how many patients with advanced non-small cell lung cancer enter clinical trials, and how can experts such as yourself help to encourage participation in trials?

Ben Creelan, MD: In my practice, about 20% of patients with advanced non-small cell lung cancer enter into clinical trials. As a physician, I think it’s my job to make this option available to them. At the same time, the trials really need to be explained in depth to these patients. Adoptive cell therapy trials provide a completely different dimension of a trial: this is a much more personalized approach if we’re talking about autologous T-cell therapies. At the same time, these treatments are quite involved, and of course, it’s not an insignificant amount of expense to manufacture cells for a patient. It requires a firm commitment from the patient to get onto these trials. I want to be able to see that the patient has local lodging for a couple of weeks after the treatment. I want to see that the patient has a caregiver. I want to make sure that the patient has financial clearance from their insurance to go ahead with this type of trial treatment. I want to show the patient that we can handle the potential toxicities— that we are experienced with this. That we have a pathway, a management algorithm, an inpatient team that’s adopted specifically to help address all the expected side effects. To me, by showing the patient that I’m here for them throughout this entire process, from signing consent all the way to getting those final CT scans throughout the course of the trial, that instills an atmosphere of mutual trust and cooperation, and that really creates a constructive and healthy patient on that trial.

Historically, we’ve had this attitude in thoracic cancers, especially lung cancer, that it’s an untreatable or incurable type of an illness. There’s even a negative stigma that the patient brought [their cancer] on themselves. It’s important that we clear the air and move beyond the idea that patients aren’t tolerant of risk when receiving clinical treatments. Many patients are more willing to tackle risk than “dyed-in-the-wool” traditional oncologists might expect. It’s important for community-based oncologists to consider referrals for these cell therapies early on, especially if the patient has an easily resectable tumor and [positive] mediastinal or supraclavicular lymph nodes and is someone who would otherwise be fit and motivated to get more intensive treatment than just your standard chemotherapy/immunotherapy combinations. The truth is those combinations fail within a year or 2 in almost all patients. It’s important for us as oncologists to really be the patient’s advocate and say, “Hey, we can always give this [TIL therapy] now and save the chemotherapy/immunotherapy as a ‘nuclear option’ later on. Right now, you could go on a clinical trial, and I’d rather make that option available to you rather than putting you through the ringer and having you come out at the end after having 2, 3, 4 lines of therapy and not really having trial options left.” I really would encourage community-based oncologists to consider referring patients for these trials as early as possible.