Oncologists who treat patients with melanoma will need to become familiar with another immunotherapy approach. For refractory metastatic disease, adoptive cell therapy is on the horizon.
“Adoptive cell therapy will offer additional hope for our patients with melanoma. We’ll likely be seeing this soon in our clinics,” said Melinda L. Yushak, MD, MPH, speaking at the 2021 Debates and Didactics in Hematology and Oncology, sponsored by the Winship Cancer Institute of Emory University,1 where she is Assistant Professor of Hematology and Medical Oncology.
Melinda L. Yushak, MD, MPH
Immunotherapy and agents targeting BRAF have boosted 5-year survival in some cohorts of patients with advanced melanoma to just over 50% in some clinical trials. “That’s tremendous, when you think about where we’ve come from, but it also means that many of our patients will still need subsequent lines of therapy,” she said.
The emerging novel regimens include tumor-infiltrating lymphocytes, T-cell receptor (TCR) T-cell therapy, and chimeric antigen receptor (CAR) T-cell therapy.
What Makes Adoptive Cell Therapy Attractive?
Adoptive cell therapy is attractive for many reasons. To -begin, the patient is receiving immune cells with direct anticancer activity and antitumor lymphocytes with higher avidity for tumor recognition. The required lymphodepleting conditioning regimens are also capable of manipulating the host microenvironment.
However, there are also drawbacks. The right target antigen must be identified, especially for TCR T cells. And, of particular importance to patients, these highly personalized therapies require time and money, and this can impact patient selection, noted Dr. Yushak.
Promise of Tumor-Infiltrating Lymphocytes
To date, in melanoma, most adoptive cell therapies have revolved around tumor-infiltrating lymphocytes. These lymphocytes recognize multiple tumor-specific neoantigens, and this may be required for response in solid tumors with high tumor mutational burdens. To manufacture these lymphocytes, tumors are excised and then chopped or enzymatically digested into small fragments, which are then cultured. Lymphocytes are grown in that culture and rapidly expanded in the presence of anti-CD3 antibodies, feeder lymphocytes, and interleukin-2 (IL-2). This is followed by further expansion to treatment levels under good manufacturing practices, after which the T cells are infused into patients who have undergone nonmyeloablative conditioning and lymphodepletion.
Treatment with tumor-infiltrating lymphocytes requires an easily accessible lesion and patience: the process can take weeks, and potentially months, for these lymphocytes to grow; for some unfortunate patients, these lymphocytes may not grow at all. Patients must also be able to tolerate the lymphodepletion regimen and post-infusion of IL-2.
A meta-analysis of 13 trials of therapy with tumor-infiltrating lymphocytes (through 2018) involving 410 heavily pretreated patients reported an objective response rate of 41%, with a complete response rate of 12%.2 Better response rates were observed in patients receiving high-dose IL-2 (43%) vs low-dose IL-2 (35%). All but one responder to high-dose IL-2 (27 of 28) remained in remission during a median follow-up of 40 months, suggesting a durable benefit.
“This type of treatment, however, has challenges in bringing it to the clinic,” Dr. Yushak acknowledged. “It’s highly individualized. It’s done by a variety of different protocols. It’s often performed only in specialized centers, so patients must travel to receive it.”
Therapy With Autologous Tumor-Infiltrating Lymphocytes
A way to avoid some of the challenges of this type of therapy may come in the form of lifileucel, a first-in-class, autologous, centrally manufactured product of tumor-infiltrating lymphocytes. In the global open-label phase II C-144-01 trial, a single infusion of lifileucel led to relatively long-lasting responses in patients who experienced disease progression while on or after anti–PD-1/L1 therapy.3
The primary endpoint, objective response rate, was achieved by 36% of patients. Complete responses were observed in 3%, and the disease control rate was 80%. After 19 months, median follow-up and median duration of response were not reached, and median overall survival was 17.4 months.
All patients had received prior immunotherapy, and 52% had received a checkpoint inhibitor plus ipilimumab. For patients with primary resistance to anti–PD-1/L1 agents, the response rate was 41%, and the disease control rate was 81%. For those who experienced disease progression on both anti–PD-1/L1 agents and ipilimumab, response rates were similar whether they received lifileucel as front-line therapy (33%) or subsequent therapy (32%).
Adverse events were as expected with lymphodepleting regimens, primarily cytopenias, fever, and fatigue. These side effects occurred early but were minimal in the long term. The timeline for manufacturing and delivering the tumor-infiltrating lymphocytes was 22 days.
“This study shows us that this is something that can be done for our patients. We can get a centrally manufactured product of tumor-infiltrating lymphocytes through good manufacturing practices,” explained Dr. Yushak. “Given these data, it’s realistic to assume that over the next year or 2, this approach will be an option for our patients in different clinics around the country.”
TCR-Engineered T Cells
T cells protect against infection by pathogens and clear mutant cells through specific recognition by T-cell receptors. The novel strategy of engineered TCR T cells has produced encouraging results in several advanced malignancies. The process involves collecting T cells from the peripheral blood, genetically modifying them, expanding them in vitro, and then infusing them into the patient after lymphodepletion.
TCR and CAR T-cell therapies differ, largely because TCRs recognize antigenic peptides that are presented by MHC molecules. Their targets are specific, including, in melanoma, MART-1, NY-ESO-1, and MAGE-A3.
In a study of 20 patients, the adoptive transfer of autologous T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201–restricted NY-ESO-1 epitope produced clinical responses in 55% and a 5-year survival of 33%.4 Also, in an HLA-A*0201–refractory population, 14 patients were treated with adoptive transfer of MART-1 TCR transgenic lymphocytes together with MART-1 peptide–pulsed dendritic cell vaccination, producing clinical responses in 69% of patients.5 The third target, MAGE-A3, was evaluated in a trial of nine patients. Five experienced clinical regression, but two patients died, apparently of necrotizing leukoencephalopathy, suggesting this may not be the best target.6
CAR T-Cell Therapy
Although success has been observed with CAR T-cell therapy in hematologic malignancies, the same has not been true for solid tumors, though efforts continue. Phase I trials are now enrolling patients with melanoma.
CAR T cells can be manufactured from both autologous and allogeneic T cells and expanded over 7 to 10 days. CAR T cells can recognize cell surface antigens in an MHC-independent manner; they can be used regardless of HLA type and can bypass mechanisms of tumor resistance, such as MHC downregulation and defective antigen processing, but they can recognize only cell surface antigens, Dr. Yushak said.
With any of these approaches to adoptive cell therapy, she continued, the challenges going forward will be to identify the appropriate patients for treatment and determine how to sequence therapy. The other looming challenge will be to ensure that eligible patients make it to treatment—considering the manufacturing wait time, the difficult conditioning, and the occasional failure to produce a usable end product. As good as adoptive cell therapy may be, it is only effective for patients who can receive it, she said.
DISCLOSURE: Dr. Yushak reported no conflicts of interest.
1. Yushak ML: Adoptive cell therapy in melanoma. 2021 Debates and Didactics in Hematology and Oncology. Presented July 30, 2021.
2. Dafni U, Michielin O, Lluesma SM, et al: Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: A systematic review and meta-analysis. Ann Oncol 30:1902-1913, 2019.
3. Sarnaik AA, Hamid O, Khushalani NI, et al: Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol 39:2656-2666, 2021.
4. Robbins PF, Kassim SH, Tran TLN, et al: A pilot trial using lymphocytes genetically engineered with an NY-ESO-1–reactive T-cell receptor: Long-term follow-up and correlates with response. Clin Cancer Res 12:1019-1027, 2015.
5. Chodon T, Comin-Anduix B, Chmielowski B, et al: Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res 20:2457-2465, 2014.
6. Morgan RA, Chinnasamy N, Abate-Daga D, et al: Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 36:133-151, 2013.