ONCAlert | Upfront Therapy for mRCC

Adoptive Immunotherapy Makes Inroads in Head and Neck Cancers, But Challenges Remain

Gina Battaglia, PhD
Published Online: Apr 13,2018
Adoptive immunotherapy has shown promising outcomes in early-stage trials for many cancers, but successful approaches in head and neck cancers will require addressing several challenges that are inherent in many solid tumors, such as creating the right homing mechanisms, achieving adequate T-cell infiltration into the tumor, and finding an antigen that will not produce off-tumor effects.

Early data on adoptive immunotherapy in head and neck cancers have shown just modest responses. However, they provide proof-of-concept that such immunotherapy can be effective, and ongoing research on optimizing adoptive immunotherapy in hematologic malignancies will help guide research for head and neck cancer, said Ezra Cohen, MD, associate director, Moores Cancer Center, and professor of medicine, University of California, San Diego, in an interview with Targeted Therapies in Oncology™.

“The success has not been as dramatic as we’ve seen in leukemia with CD19 chimeric antigen receptors [CARs] or multiple myeloma with B-cell maturation antigen CARs, but the fact that it’s been shown to work in some patients demonstrates that at least there’s a principle that appears to be true,” said Cohen. “The question becomes, how do we turn that from an unusual response to an expected response?”

Adoptive T-cell therapy for cancer involves harvesting T cells from the patient’s blood or tumor, stimulating them to grow and expand in an in vitro culture system, and reinfusing the expanded cells back into the patient with the goal of mediating tumor destruction. Development of T-cell receptors (TCRs) involves introduction of a tumor antigen–specific TCR to genetically modify T cells. These modified T cells use a complex assembly of proximal signaling molecules to achieve highly sensitive recognition of abnormal intracellular antigens, which enables them to initiate a potent, specific immune response against viruses and transformed cancer cells. By contrast, CARs are hybrid receptors formed by linking an extracellular, tumor-specific antibody fragment, a stalk-like region, a transmembrane region, and intracellular signaling domains derived from proximal T-cell signaling machinery (FIGURE).1

“The biggest difference is that CARs depend on a surface-expressed receptor or protein that can be detected by the CAR,” said Cohen. “It has to be something expressed on the surface of the cancer cell. The TCRs depend on the cancer cell essentially processing a protein and presenting it as a peptide in the context of that cell’s major histocompatibility complex.”


TCR approaches are appealing for head and neck cancers, particularly those that are virus-related, because they contain antigens that are clearly “nonhuman,” according to Cohen. A phase I study2 administered ex vivo expanded autologous T cells directed toward the Epstein-Barr virus (EBV) to 22 patients with metastatic EBV-positive nasopharyngeal cancer. Expansion of EBV-specific T cells was successful in 16 patients, who demonstrated a median overall survival (OS) of 523 days. By contrast, the patients who did not have successful T-cell expansion had a median OS of 220 days.

Early research also suggests that adoptive cell therapy could work synergistically with chemotherapy by enhancing the antitumor effect and improve immune function, which is often compromised from chemotherapies frequently used for head and neck cancer. A retrospective study3 showed that patients with head and neck squamous cell cancer (HNSCC) who received adoptive cell therapy after radical resection and induction chemotherapy had significantly longer progression-free survival (PFS) and OS than patients who received induction chemotherapy alone (PFS, 56 vs 40 months; OS, 58 vs 45 months). Additionally, the adoptive cell therapy, which involved expansion and profiling of cytokine-induced killer cells (CIKs) from peripheral blood mononuclear cells, increased the cytotoxicity of the CIKs and restored the systemic immunosuppression that occurred after the chemotherapy. The authors also noted that restoring the systemic immunosuppression that occurs with many HNSCC chemotherapy regimens can be particularly valuable for reducing infections and improving patients’ quality of life during treatment.

Recent preclinical research also suggests that TCRs increase tumor sensitivity to chemotherapy and exhibit cytotoxicity to chemotherapy-resistant tumor cells. In an in vitro study,4 adding cytomegalovirus (CMV) pp65 antigen– specific cytotoxic T-lymphocytes (CTLs) 5-fluorouracil and cisplatin (CDDP) chemotherapy demonstrated cytotoxicity against oral squamous cell cancer (OSCC) cell lines overexpressing CMVpp65 antigen, and the cytotoxicity of CMVpp65-CTL was the same with CDDP-resistant and -nonresistant OSCC cells. Further, the chemotherapeutic agents sensitized the OSCC cells to CMVpp65-CTL and did not inhibit cytotoxicity or the interferon-γ release response. From these data, the authors concluded that combining TCRs with chemotherapy could be particularly promising for patients who have CDDP-resistant tumors or who cannot tolerate high doses of CDDP.

Viruses as Targets for TCR Therapy
The rapidly increasing incidence of human papillomavirus (HPV)-positive HNSCC over the past decade has also encouraged recent research efforts toward developing effective HPV-targeted TCRs. Preliminary data from a recently completed phase I/II trial of patients with various metastatic, HPV16-positive, HLA-A*02:01-positive cancers (including oropharyngeal, cervical, anal, and vaginal) showed that administration of a nonmyeloablative conditioning regimen of cyclophosphamide and fludarabine, a single infusion of T cells genetically engineered to express a TCR targeting an HLA-A*02:01-restricted epitope of E6 (E6 TCR T cells), and systemic high-dose aldesleukin yielded partial responses in 2 of 12 patients (both with anal cancer).5 The responders had high levels of E6 TCR T-cell memory 1 month after treatment, and 7% of E6 TCR T cells were detected 10 months after treatment in a resected tumor of the patient who had a 6-month response. By contrast, tumor tissue from a nonresponder had no detectable levels of E6 TCR T cells 3 months after treatment. The researchers plan to recruit up to 18 patients for the dose-escalation portion of the study and enroll at least 41 patients for the phase II portion, provided that a clinical response is observed in at least 2 patients of the first 21 patients in the phase II portion. The primary outcome measures for the study are maximum tolerated dose, objective tumor response rate, and duration of response.

Although Cohen stated that development of adoptive immunotherapy approaches will be more challenging for virus-negative cancers, he suggested that identifying other common neoantigens, such as PIK3CA and HRAS mutations with HNSCC, and the peptides they produce, may be instrumental for developing TCRs that target these mutations. He also noted that finding targets may be somewhat easier for thyroid cancers because they tend to be more homogeneous in their genetic alterations than HNSCCs. “More than 50% of papillary thyroid cancers have BRAF mutations, so that could be a good antigen for a T-cell receptor,” said Cohen.

Using Biotechnology to Improve Identification of Target Peptides for TCR
In partnership with investigators at MD Anderson Cancer Center, researchers at Immatics US, Inc, developed IMA201 using their proprietary ACTengine approach, which engineers a patient’s T cells to express an exogenous TCR targeted to a tumor site identified by their XPRESIDENT target discovery platform. The XPRESIDENT platform improves the identification of target peptides for TCR development by analyzing peptides obtained from samples of tumor tissue and corresponding normal tissue through a combination of quantitative transcriptomics and quantitative HLA peptidomics to identify HLA peptides that are present on cells in tumor tissue and absent on cells in normal tissue.6

An open-label, first-in-human, dose-escalating phase I trial (NCT03247309) was initiated in September 2017 to investigate the safety, tolerability, and clinical activity of IMA201 in patients with HNSCC or non–small cell lung cancer (NSCLC) with an HLA-A*02:01 phenotype who have no further options for treatment or who cannot tolerate current treatments (TABLE).7 The primary objective of the study is to assess safety and to identify the maximum tolerated dose. Secondary endpoints include overall response rate (assessed using RECIST criteria and Immune- Related Response Criteria), PFS, and OS. The authors also hope to assess several translational objectives, including the persistence and functionality of IMA201 in vivo, correlative biomarkers for clinical success, and the target expression levels in the tissue.


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Adoptive Immunotherapy Makes Inroads in Head and Neck Cancers, But Challenges Remain
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