Tumor-infiltrating lymphocytes provide ‘viable option’ for advanced melanoma
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What if the next paradigm shift in cancer treatment isn’t something new? What if it is something that has been on super-low burn for an entire generation?
A group led by Steven A. Rosenberg, MD, PhD, chief of the surgery branch and head of the tumor immunology section of NCI’s Center for Cancer Research, published the first report on the use of tumor-infiltrating lymphocytes (TILs) for the treatment of melanoma in 1988.
Since then, this approach has remained relegated mostly to research facilities like the NIH and other large academic medical centers.
Source: City of Hope
Now, after 30-plus years in development, TILs soon may become commercially available for cancer treatment based on phase 1 and phase 2 trial results among patients with advanced melanoma.
As one of the earliest forms of cancer immunotherapy, TILs may benefit from the clinical testing and regulatory approval trail blazed by chimeric antigen receptor T-cell therapy, the first gene-edited adoptive cell therapy approved for commercial use in the United States.
“If approved, [TIL therapy] would be an option for approximately 10,000 [patients with] stage IV melanoma who die each year in the United States alone,” Jason A. Chesney, MD, PhD, director of James Graham Brown Cancer Center and associate vice president for health affairs at University of Louisville, told Cell Therapy Next. “Instead of going into hospice, receiving a palliative regimen of chemotherapy or another line of ineffective immunotherapy, this would be a viable option [from] which a significant proportion of patients would have a durable response.”
Chesney is one of the primary investigators for a phase 2 clinical trial of lifileucel (LN-144, Iovance Biotherapeutics), a TIL therapy regimen for patients with heavily pretreated metastatic melanoma.
“When it comes to other solid tumor types, we are testing this same exact regimen in head and neck cancer, cervical cancer, [chronic lymphocytic leukemia] and non-small cell lung cancer, which have been shown to be highly mutagenic — much like melanoma,” he added. “I believe [TILs] could be as impactful as CAR T cells have been for B-cell malignancies.”
Despite their potential to improve outcomes in advanced solid tumors — including melanoma — TILs are unlikely to be broadly used if approved by the FDA. Issues surrounding access and the toxicity of the regimen will limit use of this cell therapy to a subset of patients with relapsed or refractory disease, according to experts with whom Cell Therapy Next spoke.
TILs 101
CAR-T and TILs both are adoptive cell therapies and have many similar aspects of administration. Nevertheless, the components of the therapies are vastly different, which has a direct effect on their efficacy and safety depending on the disease they are used to treat.
Generation of TILs begins with excision of a portion of the tumor from a patient’s body.
Traditionally, fragments of the tumor are cultivated in a laboratory. According to the original NCI protocol, the tumor fragments are grown in high-doses of interleukin (IL)-2 until they form distinct T-cell populations. Then, the appropriate T-cell population for a cancer is expanded using irradiated autologous feeder cells in high doses of IL-2 over a 2-week period.
Finally, the cells are reinfused into the patient, who has undergone previous lymphodepletion chemotherapy. The regimen is completed with the administration of IV IL-2 after infusion to promote cell engraftment.
Academic researchers and companies looking to commercialize the therapy have adjusted the process over time to produce more consistent products with improved safety and efficacy.
TIL therapies can be selected or unselected.
Development of the former starts with a tumor biopsy and extraction of T cells the body already has deployed to the tumor.
These cells within the tumor are “selected to eliminate that tumor but, due to the environment and being outnumbered, they can’t eliminate the tumor and lose the battle,” Jason Bock, PhD, vice president of the therapeutics discovery division and head of biologics development at The University of Texas MD Anderson Cancer Center, told Cell Therapy Next.
Selected TIL therapy takes advantage of the body’s ability to “select” effective T-cell soldiers, and the process expands these cells from the tumor sample for use as anticancer therapy.
The unselected TIL process capitalizes on “the inherent multivalent specificity present in the immune system,” Bock said. “We have detected more than 500 distinct T-cell receptors in our TIL infusions.”
Issues with using immunotherapy in solid tumors include heterogenous composition and the amount of time it takes time for the immunotherapy response to begin. Cell therapies that target one specific antigen are susceptible to antigen loss by tumor cells, whereas TILs use multiple targets that help them overcome these evasive tactics and successfully attack solid tumors.
“In the case of solid tumors, there is no antigen that is universally expressed on all cells within a patient, let alone between patients,” Robert E. Hawkins, MD, PhD, chief strategy advisor for Instil Bio and honorary professor of medical oncology at University of Manchester, told Cell Therapy Next.
TILs appear more promising for solid tumors because of the diversity of the cell population being used as the therapeutic, he added.
“Because of their diverse population, TILs offer the broad spectrum that is required to cover all of the tumor-specific antigens that are found in a clonally diverse solid tumor,” Hawkins said. “It’s this diversity in antitumor specificity that offers the most meaningful difference between [T-cell receptor therapy] or CAR-T and TILs for solid tumors.”
The Latest Data
TILs currently are being evaluated in clinical trials for several solid tumors, with the most promising results in advanced cervical cancer and in combination with pembrolizumab (Keytruda, Merck) for patients with metastatic head and neck squamous cell carcinoma.
Regardless, melanoma remains the disease with the most robust data for these investigational treatments.
This year’s American Association for Cancer Research Annual Meeting included two presentations of the latest data on TIL therapies for melanoma. Both studies yielded encouraging safety and efficacy results.
One report evaluated a regimen developed by Instil Bio that uses autologous unselected TILs from digested tumor tissue. The company hopes that using a digested tumor rather than tumor fragments at the beginning of manufacturing process may offer the opportunity to capture more TILs and a greater diversity of TILs from the original tumor sample.
Hawkins and colleagues retrospectively analyzed outcomes of 21 patients with late-stage melanoma who received the regimen via a compassionate use protocol. The study included heavily pretreated patients who had disease progression after immune checkpoint inhibitor therapy.
Ninety-one percent of patients had disease progression after receiving anti-CTLA-4 therapy with ipilimumab (Yervoy, Bristol Myers Squibb) and 57% were dual-refractory to CTLA-4 and PD-1 blockade. Fifty-two percent of patients in the study had BRAF-mutant disease, and all these patients experienced disease progression after receiving BRAF and/or MEK inhibitors.
Median follow-up was 52.2 months, with a data cutoff date of Dec. 31, 2019.
Researchers reported an overall response rate among 15 RECIST 1.1-evaluable patients of 53%, with a 67% ORR for the entire population. Four patients (19%) had a complete response to therapy, and the overall disease control rate was 73%.
Median OS was 21.3 months (95% CI, 6.8 to not estimable) for the entire population and not yet reached for patients who achieved a complete or partial response to therapy.
Five patients (24%) had ongoing responses to therapy more than 30 months after TIL infusion, and all patients who had a complete response to therapy remained alive and disease-free as of the data cutoff date.
Safety results showed all patients experienced at least one treatment-related adverse event. No treatment-related deaths occurred.
“All the toxicity we have seen in our study is consistent with what has been reported in other clinical trials of TILs in that toxicity is mostly related to preconditioning chemotherapy and the administration of IL-2,” Zachary J. Roberts, MD, PhD, chief medical officer for Instil Bio, told Cell Therapy Next. “These toxicities tended to be self-limited and managed supportively during the inpatient period. We observed no further significant toxicities after patients were discharged from the hospital.”
Chesney presented data on a separate phase 2 study of lifileucel for patients with heavily pretreated metastatic melanoma who experienced disease progression after receiving an immune checkpoint inhibitor and BRAF/MEK inhibitors if they had BRAF V600-mutant disease.
Median follow-up was 28.1 months, with a data cutoff date of Dec. 14, 2020.
Results showed an objective response rate of 36.4%, with a complete response rate of 4.5%. Forty-four percent of patients had stable disease, for an overall disease control rate of 80.3%.
Median duration of response had not been reached (range, 2.2-35.2 months) as of the data cutoff date.
Grade 3 to grade 4 treatment-emergent adverse events — which occurred among 97% of patients — were attributed to lymphodepletion and the use of IL-2 after infusion.
Two patients died during the study, one of intra-abdominal hemorrhage possibly related to TILs and one of acute respiratory failure deemed unrelated to TILs, according to the investigator’s evaluation.
Patients in both studies demonstrated clinically meaningful responses to the TIL therapy regimen, especially given the studies were limited to patients who had disease progression despite previous therapy with immune checkpoint inhibitors, according to Warren A. Chow, MD, medical oncologist and clinical professor in the department of medical oncology and therapeutics research at City of Hope.
Chow, who specializes in the treatment of sarcomas and melanoma, said there is no standard of care for patients who progress after immune checkpoint inhibitor therapy. The only alternatives for these patients are investigational therapies available through clinical trials, he added.
“The majority of patients do respond to checkpoint inhibitor therapy,” Chow said. “But, even among those who respond, a good percentage will progress on therapy.”
The response rates in these studies were meaningful, according to Chow, who called them “good, but not great.” The durability of response was more impressive, he said, because a handful of patients remained in remission after more than 2 or 3 years.
The responses to therapy in both trials undoubtedly demonstrate clinical benefit, according to Anna C. Pavlick, BSN, MSc, DO, MBA, medical oncologist and director of the cutaneous oncology and melanoma program at Weill Cornell Medicine and NewYork-Presbyterian.
TIL therapy represents a promising alternative in a situation where choices are limited, she added.
“Their options are to go back to chemotherapy, which we know does not have a very high response rate and certainly does not provide durability,” Pavlick told Cell Therapy Next. “Knowing that you have about a 30% to 40% response rate [with TILs] is really encouraging for these patients.”
Intended for Younger Patients
Those with melanoma who progress after immune checkpoint inhibitors can benefit from therapy with TILs, but Chow cautioned that the regimen is not well-suited for all patients in this group.
The use of the TILs themselves is rather benign, and there are limited reports of adverse effects.
“The actual side effects of the TILs themselves are very mild,” Bock said.
It is the IL-2 portion of the regimen — which is crucial to the engraftment process as cells transition from the infusion bag into the body — that has presented the most problems with regard to treatment-related adverse events, he added.
“High-dose IL-2 is highly toxic and must be managed carefully,” Bock told Cell Therapy Next.
Patients with renal dysfunction would not be suitable for TIL therapy, Chow said, and IL-2 dosage adjustment would likely need to be made for older patients.
Generally speaking, Chow said patients aged older than 70 years would be poorer candidates for the therapy, unless they have the renal function and performance status of a patient aged 60 years.
“I think a large patient population for TILs [will] be the younger patients,” Pavlick said. “[They] will derive the most benefit, because this is certainly not a regimen that you’re going to consider for someone who’s older or sicker.”
Several factors make TILs less feasible for older patients, she said. First is the lymphodepletion regimen, which leaves patients more susceptible to infection over the short-term. Another concern is the risk for bleeding among patients with melanoma.
“Their tumors have a tendency to bleed and, because they’re very hemorrhagic and vascular, [it] predisposes this population to a higher risk [for] bleeding when they become thrombocytopenic,” Pavlick said.
An additional risk factor for older patients is hypotension and vascular overload from the use of high-dose IL-2.
“Many of our older patients don’t have the cardiac reserve that we think is safe for them to undergo this procedure,” she said.
“You need to make sure that you have patients who have good cardiovascular status,” Pavlick said, adding that any patient being considered for TIL therapy would undergo an echocardiogram and stress tests to ensure they can withstand possible high fevers and hypotension during treatment. A pulmonary function test also would be required before TIL therapy.
On the positive side, toxicities related to the TIL regimen usually occur within the first 2 weeks of infusion, a period in which patients on most clinical trial protocols are hospitalized for monitoring.
“When patients leave the hospital, you’re pretty much out of the worry-about-toxicity realm,” Pavlick said.
Finally, Pavlick said TIL therapy is not for patients with active brain metastases — an important consideration given the percentage of patients with metastatic melanoma who develop brain metastases.
“We worry about hemorrhage of those tumors, and we need to know that as long as the intracerebral disease is controlled, [TILs] could be a consideration,” Pavlick told Cell Therapy Next. “But if they have active disease, we don’t consider them for this therapy.”
‘Excited for the future’
More than 3 decades after the use of TILs in humans was first reported, has the time come for commercial approval of these therapies for advanced melanoma, based on the accumulated data?
“I don’t think that is for me to decide, but we will certainly use this type of therapy if approved,” Chow said.
He pointed out that TILs likely are susceptible to the same access limitations that hinder the uptake of CAR T cells. Therapies such as these will only be offered at specialized centers with experience in cellular therapies or those with a high volume of patients with melanoma.
“I think, based on encouraging data, [TILs] will be approved for commercial use.” Pavlick said.
Despite this, she agreed with Chow’s assessment that access will be limited.
“If a hospital does not do bone marrow transplant and ... is not familiar with giving high-dose IL-2 — which is a whole separate learning curve — then that institution is not going to be one that will consider providing TILs,” she said.
“As a site investigator, I have no knowledge of where things stand with the FDA approval process,” Chesney told Cell Therapy Next. “But I believe, based on the data that were revealed during AACR Annual Meeting, that TILs are a very important treatment option for patients with stage IV melanoma after receiving therapy with immune checkpoint inhibitors. As a result of these data, I believe the FDA is going to look favorably on these results.”
Roberts agreed, adding that TILs offer clear clinical benefits to patients with advanced melanoma.
“In patients with relapsed or refractory disease for whom there is no standard of care, TILs could represent a significant advance to get these patients back into deep and durable remissions,” he told Cell Therapy Next.
“I’m excited for the future of TILs because they work,” Bock said.
Years of evidence have demonstrated their efficacy, Bock added, although mostly in more academic settings. This was a similar path for CAR T-cell therapies, which were invented and simmering in academia before partnering with biotech to define a regulatory path toward commercialization.
Iovance is the biotech furthest along in commercializing TILs, according to Bock, who is consulting with the company to bring its product to market.
“They are experiencing the challenges of being the first commercial TIL candidate. It’s really hard to be first, but they have shown impressive efficacy and, despite encountering delays, are working closely with the FDA to turn this previously academic modality into a well-controlled, commercial therapeutic,” he told Cell Therapy Next. “With any luck, it will be approved next year.
“With that commercial approval and the regulatory path defined, and growing interest from biotech, I think there will be a realization that TILs are a viable therapeutic modality for commercial products as opposed to niche academic projects to publish and present at meetings,” he said.
- References:
- Chesney JA, et al. Abstract CT008. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
- Hawkins RE, et al. Abstract LB-150. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
- Rosenberg SA, et al. N Engl J Med. 1988;doi:10.1056/NEJM198812223192527.
- For more information:
- Jason Bock, PhD, can be reached at jbbock@mdanderson.org.
- Jason A. Chesney, MD, PhD, can be reached at jason.chesney@louisville.edu.
- Warren A. Chow, MD, can be reached at wchow@coh.org.
- Robert E. Hawkins, MD, PhD, can be reached at robert.e.hawkins@manchester.ac.uk.
- Anna C. Pavlick, BSN, MSc, DO, MBA, can be reached at acp9008@med.cornell.edu.
- Zachary J. Roberts, MD, PhD, can be reached at zachary.roberts@instilbio.com.
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