Lung cancer is the leading cause of cancer death in the United States.1 In the last decade, there have been significant gains in survival for patients with non–small cell lung cancer (NSCLC).2 Despite these improvements, survival in NSCLC is still poor—the 2-year relative survival was 42% for patients diagnosed in 2016—possibly due to the high tumor mutational burden and the heterogeneity seen with the disease.1,3

Despite gains in survival, the 2-year relative survival for patients diagnosed with NSCLC in 2016 was 42%. There is a substantial unmet need for patients with NSCLC who do not respond or have progressed on immune checkpoint inhibitors.

Checkpoint blockade inhibitors have dominated the treatment landscape, markedly improving clinical outcomes for some patients with NSCLC and other solid tumors. However, there is still a substantial unmet need for patients who do not respond or have progressed on immune checkpoint inhibitors.4 A key reason for immune checkpoint failure is extrinsic suppression of infiltrating immune cells by the tumor microenvironment. Therefore, new strategies are needed for those who experience treatment failure with checkpoint inhibitors.

Adoptive Cell Therapies

There has been growing interest in another class of immunotherapy—adoptive cell therapy (ACT)—that exploits the body’s ability to recognize and eliminate cancer cells. In ACT, a patient’s own T cells are either isolated based on their tumor-specific antigen recognition or are genetically modified to target certain molecules present on cancer cells.5 These cells are then expanded ex vivo and infused back into the patient.

ACT has several advantages compared with other immunotherapy options that rely on the active in vivo development of antitumor T cells to mediate cancer regression.6 With ACT, large numbers of antitumor lymphocytes with high recognition of the tumor can be grown in vitro. This allows for the manipulation of the host before cell transfer to provide a favorable microenvironment that better supports antitumor immunity through lymphodepletion.

Chimeric antigen receptor (CAR) T-cell therapy is the only ACT thus far to be approved by the U.S. Food and Drug Administration (FDA), and its use is currently limited to hematologic malignancies. Nonetheless, many other indications and cell types are currently under investigation.7 These include tumor-infiltrating lymphocytes (TIL) and T-cell receptor (TCR) therapy.

Response Rates to Adoptive Cell Therapies

CAR T-Cell Therapy

In CAR T-cell therapy, autologous T cells are genetically redirected and reprogrammed with CARs that target molecules expressed on malignant cells.8 CARs contain an extracellular antigen-identifying domain, which is constructed by fragments of monoclonal antibodies identifying a particular protein on the cell membrane of the cancerous tumor—for example, epidermal growth factor receptor (EGFR) on solid tumor cells or CD19 on B cells—and an intracellular stimulating domain that provides the TCR signaling to trigger CAR T-cell activation and function. Although the first CAR T cells were fairly simplistic, further generations have added costimulatory domains that improve CAR T-cell expansion, function, persistence, and antitumor activity.8

In patients with certain types of leukemia and lymphoma, CAR T-cell therapy has demonstrated durable disease remission—or even cure—by targeting the protein CD19, an antigen found on the surface of B cells. This has shifted the treatment landscape for lymphoid malignancies, especially diffuse large B‐cell lymphoma and acute lymphoblastic leukemia.9 Currently, there are several FDA-approved CAR T-cell products; three of these target CD19, and the FDA recently approved the first CAR T-cell product targeting B-cell maturation antigen for the treatment of multiple myeloma.10–14

CAR-T relies on a protein to be stuck on the surface of the tumor cell. …Most of the time, we don't have a protein on the surface of a tumor cell that we can just wipe out with impunity; otherwise, the patient risks off-tumor, on-target toxicity.Ben Creelan, MD

Despite the success of CAR T-cell therapy in hematologic malignancies, its use in solid tumors is still in its infancy.15 So far, no cell surface antigen with comparable properties as CD19 has yet been identified within solid tumors, although many tumor-associated antigens have been extensively investigated, including HER2, EGFR, WT-1, and mesothelin.16,17

An ideal molecule for CAR targeting should be overexpressed on the cancer cell surface of many patients, with zero or low expression in normal tissues. “CAR-T relies on a protein to be stuck on the surface of the tumor cell,” explained Ben Creelan, MD, a thoracic oncologist at the Moffitt Cancer Center, Tampa, Florida. “Most of the time, we don’t have a protein on the surface of a tumor cell that we can just wipe out with impunity; otherwise, the patient risks off-tumor, on-target toxicity.”

CAR T cells return to the bloodstream and lymphatic system, so they have more contact with blood tumor cells. In solid tumors, however, CAR T cells may not be able to penetrate tumor tissue through the vascular endothelium due to the lack of expression of chemokines involved in the trafficking of T cells into tumor tissues and the presence of dense fibrotic matrix in solid tumors.16 Another obstacle with the use of CAR T-cell therapy in solid tumors is a phenomenon known as “tumor antigen escape.” Tumor cells can escape killing by expressing alternative forms of the target antigen that lack the extracellular epitopes recognized by CAR T cells.3

CAR T-Cell Therapy in NSCLC

Several early clinical trials using CAR T-cell therapy in NSCLC have produced lackluster results, with several terminated or remaining unpublished. The most commonly studied target antigens include PD-LI, EGFR, mesothelin, mucin 1, PSCA, carcinoembryonic antigen, and HER2. 3,18–20 In one phase I trial of patients with EGFR-positive relapsed or refractory NSCLC, EGFR-targeted CAR T cells showed modest efficacy; of 11 patients, 2 had a partial response and 5 had stable disease.21 Other trials are attempting to limit toxicity by confining the infused CAR to the pleural space.22

Challenges With CAR T-Cell Therapy

In addition to efficacy concerns with CAR T-cell therapy in solid tumors, other challenges exist, including cytokine-release syndrome; on-target, off-tumor toxicity; neurologic toxicity; and anaphylaxis. Cytokine-release syndrome, the most frequent adverse event associated with CAR T-cell therapy, is estimated to affect 50% to 90% of patients in major clinical trials.23 It is most common within the first days after product infusion. This systemic inflammatory condition originates from direct activation and expansion of T cells after the interaction with target cells, leading to the production of cytokines such as TNF-alpha and INF-gamma.

The real challenge [with CAR T-cell therapy] in solid tumors is reaching a cell dose capable of response, while managing the off-tumor, on-target toxicity, which can be persistent and severe.Ben Creelan, MD

The severity of cytokine-release syndrome can vary widely from patient to patient, from self-limiting flu-like syndrome to life-threatening multiorgan dysfunction. However, Dr. Creelan noted that clinicians have learned to anticipate and manage cytokine-release syndrome. “At Moffitt, we recently treated our 500th patient with CAR T-cell therapy. We have developed streamlined algorithms and management guidelines for the toxicity due to CARs,” he said. “Most patients are willing to withstand the storm of CAR toxicity when it comes to cytokine-release syndrome. The real challenge in solid tumors is reaching a cell dose capable of response, while managing the off-tumor, on-target toxicity, which can be persistent and severe.”

The cost of therapy—estimated, in total, to be around $450,000—and time to manufacture the product are other legitimate concerns.24 “The time to production for autologous T cells is approximately 4 to 6 weeks to harvest the white blood cells, manufacture the T cells, and infuse them back into the patient,” explained Dr. Creelan. “That timeline can be an issue.”

Role of TIL in Tumor Microenvironment

TIL therapy is another adoptive cell therapy currently under investigation for the treatment of NSCLC. The interest in tumor-infiltrating lymphocytes having therapeutic potential spans decades, with studies beginning in the 1980s.25,26,27

TILs are a collection of heterogenous lymphocytes that have penetrated the stroma of a tumor.28,29 Important in the tumor microenvironment, TILs consist of numerous antitumor effector or regulatory T cells and are key players in the host’s immune response to tumors. These tumor-specific T cells are activated through encounters with tumor-associated antigens that are presented by specialized antigen-presenting cells, including dendritic cells. The most consistently beneficial TILs appear to be cytotoxic T lymphocytes—CD8-positive TILs—that specifically recognize and destroy target cells by recognizing tumor-derived antigenic epitopes.

What Is TIL Therapy?

While other types of ACT utilize circulating T cells from the blood, TIL therapy harvests neoantigen-directed T cells that are isolated from a tumor biopsy. Once the TILs are isolated, they are cultured and expanded. The patient receives a lymphodepleting conditioning regimen that diminishes immunosuppressive cells, and the TILs are then infused into the patient.

Because they recognize antigens specific to the individual patient’s tumor—somatic tumor-specific mutations—TILs are less likely to cause off-target toxicity compared with CAR T cells.4 Additionally, there is a lower risk for cytokine-release syndrome compared with CAR T-cell therapy, said Dr. Creelan. “The TILs use your own native repertoire of T cells and are not genetically modified like CARs,” he explained. “So, you have much less potential for the cytokine storm that can occur with CAR T, as those genetically modified T cells proliferate quickly.”

Use of TIL Therapy in Other Tumor Types

TIL therapy has demonstrated efficacy and safety in several patient populations with high unmet medical need, including unresectable and metastatic melanoma; relapsed, refractory or persistent cervical cancer; and head and neck squamous cell carcinoma.30–32

The most extensive and robust data with the use of TIL therapy are in the treatment of melanoma.33 In a National Institutes of Health (NIH) study, 93 patients with metastatic melanoma received TIL plus IL-2 following a preparative lymphodepleting regimen. The treatment led to durable complete responses in 22% of patients, and 95% of these complete responses were ongoing beyond 3 years.34 In a prospective, phase II open-label, single-arm multicenter study in 66 patients with advanced melanoma progressing on immune checkpoint inhibitor therapy (and BRAF inhibition with or without MEK inhibition if BRAF V600 mutated), lifileucel showed a response rate of 36.4%.30 Lifileucel, an autologous TIL cell therapy, was produced from harvested tumor specimens using a streamlined 22-day process. At 33.1 months of follow-up, the median duration of response has not been reached for this cohort.54 A phase III study is underway that compares the current standard of care with ipilimumab to TIL in patients with advanced melanoma; the role of TIL as possible first-line therapy in combination with anti–PD-1 is an additional subject of clinical trials.33,35

The success achieved with TIL therapy in melanoma is encouraging for its use in NSCLC due to the similarities between the two malignancies. NSCLC has one of the highest clonal mutation burdens of all cancers through exposure to carcinogens in tobacco smoke—second only to melanoma.4,36 In patients with melanoma, the tumor mutational load and predicted neoantigen load have been shown to correlate with clinical outcomes for TIL therapies, suggesting that TIL efficacy is driven through neoantigen-reactive T cells within the product.37 As Dr. Creelan pointed out, the immune microenvironment within the lung tissue has evolved to be the body’s strongest line of defense to fight foreign proteins. “Because the lungs are the first barrier to fight against pathogens, we see some of the most robust antigen-specific T cells within the lung.”

TIL Therapy in NSCLC

PD-1/PD-L1 inhibitors as first-line therapy, with or without platinum-based chemotherapy, have substantially improved overall survival in patients with NSCLC.38–41 However, 45% to 50% of patients with metastatic NSCLC do not achieve an optimal response with chemotherapy and checkpoint inhibition—and almost three-quarters of patients experience disease progression or die within 12 months of starting treatment.4 For those with resistant disease following PD-1/PD-L1 inhibitor plus platinum doublet chemotherapy as first-line treatment, there is currently no standard second-line treatment.4

In this early lung cancer trial, we saw responses, including complete responses, in patients who have progressed on PD-1 inhibitors and had subsequent tumor growth. The key point is that TIL can work in this population.Ben Creelan, MD

Early studies of TIL in NSCLC began in 1996.42 However, recent improvements in the manufacturing process—including the use of good manufacturing practices to isolate and expand TIL cultures using state-of-the-art protocols—coupled with the incorporation of a preconditioning regimen have increased the feasibility of TIL therapy.36

Recently, a phase I trial investigated the combination of TIL therapy and anti–PD-1 therapy in patients with metastatic NSCLC.43 Patients with no prior exposure to PD-1 inhibitors had their TILs harvested from a resected metastatic lesion before receiving four doses of nivolumab. Those patients with tumor enlargement or new lesions (n = 13) proceeded to lymphodepletion, TIL infusion, and attenuated IL-2; then, nivolumab was resumed for up to 11 doses to augment TIL persistence.

Of the 13 patients who received TIL therapy, 2 achieved durable complete responses and 3 maintained a clinical remission by local ablative therapy of an isolated new lesion post-TIL. “In this early lung cancer trial, we saw responses, including complete responses, in patients who have progressed on PD-1 inhibitors and had subsequent tumor growth,” said Dr. Creelan, the lead study author. “The key point is that TIL can work in this population.” The most common nonhematologic adverse events of the treatment regimen included hypoalbuminemia, hypophosphatemia, nausea, hyponatremia, and diarrhea.

A phase II study is now underway to evaluate the efficacy of TIL in metastatic NSCLC, including patients without an actionable driver mutation following a single line of approved systemic therapy consisting of an immune checkpoint inhibitor, chemotherapy, with or without bevacizumab.44

Considerations With TIL Therapy

TIL therapy is a one-time treatment option, which alleviates the risk of repetitive or persistent adverse events. The personalized immunotherapy can come at a substantial cost, though, because a patient-specific infusion product must be produced in highly specialized cGMP facilities.33 Additionally, the production time of a TIL product has historically been too long for some patients with rapidly progressive disease.33 However, “traditionally, TIL production was 6 to 7 weeks, but now the timeline is down to 22 days or so,” said Dr. Creelan. “Overcoming this hurdle has been an important milestone in making this therapy feasible for patients in regular practice.”

The most common toxicities during TIL therapy are associated the lymphodepleting preparative regimens and the subsequent IL-2 after TIL infusion. Because of the risk of toxicity, TIL therapy usually requires inpatient hospital monitoring during the IL-2 phase. If lymphodepletion chemotherapy is added to this inpatient stay, it can result in a median duration of as long as 20 days.45 Nonmyeloablative lymphodepleting chemotherapy may cause hematologic and nonhematologic toxicities, including neutropenic fever, diarrhea, hyperbilirubinemia, and fludarabine-induced neurotoxicity. While high-dose IL-2 therapy toxicity is usually transient, it requires close monitoring in hospital setting; capillary leak syndrome after IL-2 administration is common. High-grade toxicity attributed to the TIL infusion product itself is “exceedingly uncommon.” Patients may develop transient dyspnea, chills, and fever shortly after infusion of TIL.

We need to dispel the stodgy idea that this population is ineligible for high-risk, high-reward treatments.Ben Creelan, MD

A Path Forward

Despite the adoption of immune checkpoint inhibitors for the treatment of advanced NSCLC, there is still a significant clinical need for additional treatment options. ACT therapies appear to be an optimal candidate for the treatment of NSCLC; however, enrolling patients for clinical trials has been a hurdle for researchers. “As medical oncologists, we are lousy at planning ahead,” conceded Dr. Creelan. “We often pick the ‘lowest-hanging fruit’ as the next treatment option instead of strategically planning. The truth is that TIL and other ACT therapies require a reciprocal discussion with the patient to explain the treatment process and assess their motivation level.”

Additionally, he worries that the historical nihilism about lung cancer as a terminal diagnosis affects how treatment of advanced NSCLC is approached. “We need to dispel the stodgy idea that this population is ineligible for high-risk, high-reward treatments. Patient advocacy groups are working to change physician attitudes.”

The “high reward” of TIL therapy cannot be overlooked; as Dr. Creelan noted, some patients with melanoma who were treated with TIL therapy in the 1980s are still in remission today. “While normal effector T cells only last 7 days, our memory T cells can engraft and persist for 60 to 70 years.” Ultimately, collaboration between researchers, cell therapy experts, and community practitioners will benefit the advancement of study in this facet of immuno-oncology for patients with advanced NSCLC.


Dr. Creelan has served in a consulting or advisory role for Abbvie, AstraZeneca/MedImmune, E.R. Squibb Sons LLC, Achilles plc, and KSQ Therapeutics; has participated in a speakers' bureau for AstraZeneca/MedImmune; has received institutional research funding from Bristol-Myers Squibb, Iovance Biotherapeutics, and Prometheus Laboratories; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca.


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