Daniel Johnson, MD, discusses the use of TIL therapy in melanoma, including patient selection, sequencing, timing, and emerging applications beyond skin cancer.
For oncologists considering tumor-infiltrating lymphocyte (TIL) therapy in advanced melanoma, key questions center on who should receive it and when to act. Appropriate candidates are patients whose disease has progressed on checkpoint inhibitors, and, if BRAF mutated, targeted therapy. However, the decision-making hinges on starting the evaluation process early enough to overcome lengthy preparation times and avoid rapid disease progression, according to Daniel Johnson, MD.
“My approach for all patients with metastatic melanoma [who] have [disease] progression on combination immunotherapy who have exhausted their standard of care [SOC] options is to start the TIL evaluation at that point, whether they’ve received BRAF-targeted therapy or not,” Johnson said in an interview with OncLive®.
In the interview, Johnson, a medical oncologist and director of the Center for Innovative Cancer Therapies at Ochsner MD Anderson Cancer Center, discussed how he approaches patient selection for TIL therapy, when to initiate the referral and workup process, and how to sequence the therapy alongside checkpoint inhibitors and targeted agents. He also highlighted logistical considerations, institutional requirements, and ongoing research aimed at expanding TIL therapy beyond melanoma.
Johnson: Lifileucel [Amtagvi] is approved in patients with metastatic melanoma who’ve been previously treated with PD-1 blockade, and, if [their disease is] BRAF mutation-positive, who have also been treated with BRAF-targeted therapy.1 Due to the complexity of delivering the treatment, along with potential toxicities, this really should be a last resort option after all SOC has been exhausted. It’s important to exhaust immune checkpoint inhibitors, [both] SOC and on trial before TIL therapy, because it takes a while after you get lymphodepleting chemotherapy for the natural T-cell population to recover. In patients who get TIL therapy and then don’t respond as we hoped for, their other immunotherapy options may be more limited for an extended period.
Also, one issue that we run into is [that] patients who have been heavily pretreated and have BRAF mutations have much more aggressive disease at that time. The process to prepare a patient for TIL therapy includes financial approval, medical clearance, pulmonary function tests, cardiac workup, infectious workup, et cetera, [before we can] get the TIL harvested, send the specimen off, and have the TIL grown and processed, which can take 4 to 6 weeks. The whole process, including financial approval, at minimum, takes 2 to 3 months, which is a long waiting time. What we and other TIL centers have found is that it’s nearly impossible to have good outcomes for patients with BRAF-mutated melanoma [who] are already progressing on targeted therapy. When BRAF-mutated melanoma becomes resistant to BRAF/MEK inhibitors, the disease becomes very aggressive. It’s important to get these patients referred to a TIL center early to start the authorization process, because in general, those patients are not going to do well if you wait until after they’re progressing.
Fortunately for Ochsner, we already had everything in place, infrastructure-wise, for TIL therapy.2 We have great melanoma surgeons––David T. Pointer, Jr, MD; and Russell E. Brown, MD––who have had TIL experience and are familiar with TIL from their prior training. We also already had a very active cellular therapy lab because we do bone marrow stem cell transplants. We have an active CAR [chimeric antigen receptor] T-cell therapy program as well. We also already had a bunch of SOPs [standard operating procedures] in place for cellular therapy because of our CAR T program, and those protocols are very similar to [those required for] TIL [therapy]. We had a lot in place already that is needed to do TIL therapy.
The main part with TIL that’s unique and most centers don’t have a ton of experience with is managing the high-dose IL-2, which is the growth factor given after TIL infusion. But with some onboarding with Iovance [Biotherapeutics], the company that [manufactures] lifileucel, and our partner, [The University of Texas] MD Anderson Cancer Center in Houston, our inpatient oncology team was very well prepared for our first patient [whom] we treated with that [therapy]. The most important thing in preparation for new centers that want to be a TIL center is to not only get all that infrastructure in place that’s needed, as far as making sure surgeons know what to do from a protocol and harvest standpoint, and making sure you have the ability to store cellular therapy products and liquid nitrogen, but to have really good SOPs and protocols to develop with Iovance regarding the initial workup, the lymphodepleting chemotherapy, the TIL harvest and infusion, and, very importantly, the management of high-dose IL-2 toxicities. That’s really all that’s needed to be a TIL center.
I’m typically starting all patients with metastatic unresectable melanoma on a combination of immune checkpoint inhibitors, whether they have a BRAF mutation or not. The data from the SECOMBIT [NCT02631447] and DREAMseq [NCT02224781] studies have shown that it’s best to start with immunotherapy. Up front, that’s what I’m starting with for most patients [who] don’t have a contraindication, and whether I use nivolumab [Opdivo]/ipilimumab [Yervoy] or relatlimab-rmbw and nivolumab [Opdualag] is pretty nuanced, but if a patient has progression of disease on a combination of immune checkpoint inhibitors, that’s when I start the evaluation process for TIL therapy. The FDA label does say that [patients with] BRAF [mutation] have to have exposure to BRAF and MEK inhibitors––that is required in order to get approval. So oftentimes what I’m doing is starting the workup process and the financial authorization process while a patient may be getting started on targeted therapy in the second line for BRAF-mutated melanoma, but it’s important that the initiation of TIL should be started prior to resistance of the targeted therapy in those patients due to the rapidity of progression once that happens. Oftentimes we’re starting the process for TIL therapy, starting targeted therapy, and then potentially holding it while getting the TIL process started, getting the TIL harvested, using the targeted therapy to bridge patients to get TIL infusion.
It’s a very good question that has not been figured out yet. Every center is going to have a different approach. Probably wanting to be teed up for TIL is most important, because it’s that 2- to 3-month lag that patients can’t wait for. You don’t know whether a patient is going to respond for the usual [length of time], which is about 15 months to targeted therapy, or if they’re going to respond for 3 months or 3 years. I would get started early with the harvest and approval process and then utilize targeted therapy as a bridge. Now, when to pull the trigger on the actual treatment, the actual admission for the lymphodepleting chemotherapy, infusion, et cetera, that’s probably going to be patient specific, and it may be that you stay on targeted therapy until patients show signs of progression. It’s probably going to [require] a discussion of the risks and benefits with the patient at that point.
The discussion with patients is pretty similar to my discussion before starting immune checkpoint inhibitors. The goal of all T-cell–based immunotherapies, which include immune checkpoint inhibitors and TIL therapy, is to induce a memory T-cell response, and this is what provides a durable response for 5 years. It’s important for patients to know the response rates. What’s the chance of success? For TIL therapy, response rates hover around 30%, and the 5-year overall survival rate is around 20%, so it’s important for patients to know that the majority of people are not going to have those durable responses that are lasting 5 years. However, if a patient has a response, the median duration of response is over 3 years, so most of them are very [durable]. My discussion with regard to TIL therapy is similar to my discussion for any T-cell–based immunotherapy. It’s really what the chance of success is, and then when there is a response, oftentimes there’s no ceiling to how long those responses last.
The usual suspects when it comes to tumor types that respond to immune checkpoint inhibitors. [So, those with] higher tumor mutation burden and cancers that are known to have T-cell infiltrates. That’s the logical next step for TIL therapy as far as different tumor types outside of melanoma. Cervical cancer and non–small cell lung cancer [NSCLC] seem to be the most promising, with response rates ranging from 20% to 40% with TIL therapy. The biggest limitation for TIL in other tumor types will be the toxicity profile, particularly [in] patients with NSCLC [who] are heavily pretreated, [as] they have more comorbidities, are usually older,…and, given their prior treatments that they’ve typically had, [are] probably going to be less likely to tolerate high doses of lymphodepleting chemotherapy and IL-2. Moving forward, that’ll be the biggest limitation. Now, there are novel TIL regimens that are very exciting that use lower doses of lymphodepleting chemotherapy, more [like] the dosing used for CAR T cells, which makes sense, and [those that] use less toxic growth factors like IL-15. That’s needed in that space to make it more tolerable. Improvements to TIL are coming, which should hopefully open it up for a lot of different cancer types.
