In the first interview of this series, Allison Betof Warner, MD, PhD, reviews the mechanistic rationale of tumor-infiltrating lymphocytes and considers their potential use in the management of solid tumors.
Tumor-infiltrating lymphocytes (TILs) are cells harvested from a patient’s tumor and grown in large numbers in a lab. After being trained to recognize and attack tumor cells, they are reintroduced to the patient to aid the immune system in attacking cancer cells. This adoptive cellular therapy is under investigation in several clinical trials, including C-144-01 (NCT02360579): a global, multicenter study of autologous TIL LN-144 followed by interleukin 2 (IL-2) in metastatic melanoma.
Ahead, Allison Betof Warner, MD, PhD, a medical oncologist specializing in melanoma at Memorial Sloan Kettering Cancer Center in New York, New York, discusses the rationale behind tumor-infiltrating lymphocytes and identifies their potential in the solid tumor treatment landscape. Dr Warner looks toward the future clinical utility of tumor-infiltrating lymphocytes as neoadjuvant or frontline therapy options.
Targeted Oncology™: What role do endogenous tumor-infiltrating lymphocytes play in normal biological function?
WARNER: The role of endogenous TILs in normal [biological] function is that tumor-infiltrating lymphocytes or TILs ideally would come into a tumor, recognize that that tumor is foreign, and be able to kill those cancer cells. Where that sometimes goes wrong is either the TIL may not make it into the tumor, or they may not recognize that that is an antigen that they should attack.
Targeted Oncology™: What is the mechanism of action for tumor-infiltrating lymphocytes in producing an antitumor effect?
WARNER: TILs produce an antitumor effect simply by T cell–mediated cell death. That again requires an activation signal and recognition by the TIL that that is a target for cell death. Once that target has been established, then an active TIL simply carries out its normal biologic function and mediates lymphocyte-induced cell death.
Targeted Oncology™: How does TIL therapy differ from other available immunotherapies such as immune checkpoint inhibitors or CAR T-cell therapy?
WARNER: TIL therapy is a little bit different from other immunotherapies that we think about. Checkpoint inhibitor therapy, for example, is an IV [intravenous] medication that we will give patient[s] with different types of tumors and can activate the native T cells that exist in a person's body. That [therapy] counts on those T cells being able to recognize and find the tumor, and actually get into the tumor to do their cell killing. Sometimes checkpoint blockade does not work even if the T cells are activated because those T cells can't find the tumor [or] can't penetrate into the tumor.
The idea behind TILs is that we ... take that barrier out. We take the tumor out and we find the TIL that already made their way into the tumor. We overcome that hurdle of [identifying] which lymphocytes could actually find the tumor, and which could get in there. We identify the TILs that actually made it into the tumor. Then, those are expanded million- and billionfold. Then, [they are] given back in high doses to the patient.
CAR T is a slightly different type of therapy but is yet again a cellular therapy similar to TIL. In CAR T, instead of taking out a piece of tumor, you take out patients’ lymphocytes via an apheresis procedure. Then they genetically engineer those cells to express a receptor that helps recognize the tumor. One of the challenges with CAR T can be that we need to know what antigen those TIL or T cells are looking for. If you don't have a known, common shared antigen, it's hard to know what to engineer those T cells to express. In TIL, what is slightly different is that we take out the native T cells. They may be all against different targets, targeting different antigens. That's OK. We grow all of them and hope that some of them are tumor-specific antigens that will be the effective [at] killing the tumor.
Targeted Oncology™: In terms of potential durability of remission or duration of response, how does TIL therapy compare to other treatment modalities?
WARNER: One of the advantages of cellular therapy, whether it is CAR T-cells or TILs, is the idea that this is really supposed to be a one-time treatment. It's a big lift upfront. There is a lot of toxicity in the first week or two. It can be a real challenge for patients to get through in terms of [adverse] effects. But it's only done once. The data thus far that we have seen from TIL therapy in melanoma are that [in] the patients who respond, for the most part those responses are quite durable. From some of the TIL products that we've seen, we are seeing responses well over 18 months. For patients who are responding, the median duration of response seems to be—or at least more than half the patients are still responding after—12 months [following] that one-time dose. That's different from checkpoint blockade, where we have to give dose after dose after dose. There is that ... added advantage or built-in advantage of self-therapy. We have the potential for it to be a one-time therapy. Now as we've [become] more advanced in the CAR T-cell world, we've seen some patients getting reinfusion of CAR T. We likely will see this someday with TILs. But the general idea here is that one treatment for responders should produce a durable response.
Targeted Oncology™: Can you expand more upon how TILs may provide advantage in terms of tackling tumor heterogeneity or high mutational burden?
WARNER: TILs may overcome the issue of tumor heterogeneity or high mutation burden by being polyclonal. When we think about, for example, CAR T-cell therapy or TCR [T-cell receptor] therapy, we are engineering a cell to express a particular receptor that is only looking for one antigen. That tumor may express that antigen in some parts but not others. You might see effective cell killing in one part that expresses that antigen. But then you have a whole part of the tumor that may in fact be resistant to that therapy and could grow in that setting. The idea behind TIL is that we are taking out multiple, different types of T lymphocytes that target all kinds of different antigens [and] express different receptors. Therefore, one might target one region of the tumor, and another might target another region of the tumor. The idea being that hopefully, this overcomes some of those ... issues.
High mutational burden is the same issue, where there may be a large number of tumor specific neoantigens due to that high number of mutations. The polyclonal nature of the T cells, the ability to see different antigens [and] recognize different antigens, may be really important to actually treating the whole tumor.
Targeted Oncology™: Targeting single tumor antigens has been associated with certain limitations, including antigen loss, which can lead to tumor evasion and the development of treatment resistance. How might TIL therapy provide an alternative strategy to overcome these limitations?
WARNER: TIL therapy may help overcome some limitations to immunotherapy. One of those is antigen loss. Now, if you only have active lymphocytes against one antigen and that antigen is lost or downregulated, then those lymphocytes are no longer going to be activated against that tumor. The tumor is not going to be killed by the T cells. In contrast, when we use this polyclonal approach, while a tumor might lose one particular antigen, if it still expresses other antigens that the TILs recognize, you could still have tumor killing. Now, if you have true downregulation of antigen expression or MHC [major histocompatibility complex] class I loss, that may not be addressed by TIL therapy. But that's something that we need to learn going forward. Another barrier that this really overcomes is getting the TILs that can actually find the tumor. That really is the idea behind TIL therapy: overcoming that barrier that we have with checkpoint blockade where some of the T cells can't even find the tumor in the first place or don't know what antigen to look for.
Targeted Oncology™: The use of high-dose IL-2 supports the growth and activity of TILs. But conversely, it can also induce toxicity. In your practice, how do you monitor for toxicity associated with high-dose IL-2 during TIL therapy?
WARNER: High-dose IL-2 is really important to TIL therapy, at least as it exists right now. But [it] absolutely comes with the caveat of a lot of toxicity. We know that IL-2 serves as a boost and a survival signal for infused TILs. For that reason, at least one or a few doses are really important. That being said, different from the days when we gave true high-dose IL-2 therapy, the IL-2 is not the therapy here. It is the supportive medication for the TILs. We don't need to push past those points of severe toxicity. If a patient is becoming hypotensive and they are not rapidly responding to fluids, we don't give them more IL-2. We monitor urine output very, very closely. If urine output starts dropping below 50 ccs an hour, and certainly below 30 ccs an hour despite fluid boluses, that is an indication to stop IL-2. If patients develop hypoxia from capillary leak, [that is] yet another reason to stop IL-2. In the older days when we used IL-2 as a therapy, we would just keep treating. We would push through these toxicities because we knew that patients needed more of the actual therapy. In this case, where it's being used as a supportive medication, there are no data that say more IL-2 is better. We know that patients need some IL-2. But once we've hit that toxicity point, we typically stop.
Targeted Oncology™: How often do IL-2–related toxicities occur during TIL therapy?
WARNER: IL-2 toxicity is exceptionally common. Most patients will develop fevers. Many, if not most, will develop shaking chills or rigors. The hypotension, hypoxia ... are less common. Somewhere [around] 11%, 15%, or 20% [of patients] will develop hypotension depending on what study you look at. Hypoxia is probably in that same, general region and certainly depends on how much fluid they got before the IL-2 and during the IL-2 infusion. Unpleasant, the fevers, the rigors [are] exceptionally common. I tell every patient just to expect that it is going to happen and then to be pleasantly surprised if it does not. The other [toxicities] are more scattered patient to patient.
Targeted Oncology™: How might the next-generation TIL therapies, which are currently under investigation, help to reduce the potential for toxicities related to high-dose IL-2 support?
WARNER: This is what's really exciting about TIL therapy. I think this is generation one of many generations to come. The current TIL therapies require that stimulatory signal from IL-2 to survive and take up home after infusion. Some of the newly engineered technologies are built-in with ... costimulatory signals or express alternative cytokine that would potentially obviate the need to even give IL-2 at all. [There is] much to learn about this. I think it's too early to say for sure that that is going to work or be an effective strategy. But certainly, there are many of these TIL products in development and we are really excited to get our hands on them and start trying them. One of the biggest barriers to TIL therapy for patients is the ability to make it through the IL-2 and to withstand that toxicity. If we can cut down on that using these engineered TIL products, this will be a much more accessible therapy to patients.
Targeted Oncology™: What does TIL therapy offer in terms of being an alternative therapeutic strategy for patients?
WARNER: I think there are many advantages to TIL therapy. We are still learning [more] as we are going for sure ... After progression on standard checkpoint blockade, there just is not effective therapy for most patients. There may be therapy that could slow tumor growth. There may be therapy that causes stable disease. But very few patients who have progressed past standard checkpoint blockade will achieve a durable response or even a complete response to really any therapy. TIL therapy has that possibility. That's what's really unique about this therapy: the idea that we could give a therapy once and a patient could have a durable response [and] long-term disease control. Really in the past, that has only been offered by checkpoint blockade. This is an alternative immunotherapy strategy that may achieve that goal in a population that is typically very resistant to any other therapies.
Targeted Oncology™: How might tumor-infiltrating lymphocytes impact the future treatment landscape?
WARNER: We expect that TILs are going to change the landscape dramatically. There are a variety of trials of TILs in different settings. Most commonly, TILs are studied in the checkpoint-refractory setting. But there are ongoing trials with TILs in the neoadjuvant setting [or] giving people TILs plus checkpoint blockade before surgery, as well as in frontline metastatic disease. I think we need to really think hard about what the toxicity of this therapy is and whether a frontline strategy is really the best approach right now, particularly if checkpoint blockade is available. But it certainly is being explored and I think we need to see the results of those trials to really make a decision about the best role for this therapy.
Certainly, as we are able to genetically engineer TIL to potentially give this as an outpatient therapy and avoid IL-2, you are then absolutely thinking about a much broader patient population that could be treated with TIL therapy and certainly in earlier lines of therapy as well. I think it's a little too early to know for sure whether that is going to be the strategy that we use as standard of care in the future. But those are definitely strategies that we are excited about and are actively exploring.