Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related, highly chemo-radiosensitive malignancy. However, one-third of patients are considered to be incurable because of metastatic or recurrence disease. Expression of antigenic viral proteins by malignant cells constitutes a good target for immunotherapeutic strategies. Although the majority of clinical data have been obtained in the setting of EBV-related posttransplant lymphoproliferative disorders, this therapeutic approach has been more recently applied to solid tumors.
We and others have implemented T-cell therapy programs for patients with NPC failing conventional treatment. The feasibility of expanding EBV-targeted cytotoxic T lymphocytes (CTL) by stimulation with EBV-transformed lymphoblastoid cell lines (LCLs) has been demonstrated, and clinical trials were conducted, based on administration of 2 or more doses of EBV-CTLs (4-40 x 107/dose), supported by in vivo rhIL-2 infusion and, in some cases, pre-treatment with lymphodepleting chemo or immunotherapy.
So far, more than 60 patients were treated in different centers for refractory/relapsed advanced NPC, and about 20% objective responses, including some complete responses, were observed, with no or limited adverse events. These results are encouraging, although further improvements to the laboratory and clinical protocols are clearly necessary to increase anti-cancer activity. One approach that our center has lately pursued is to test the efficacy of CTL therapy in earlier stages of disease, in particular immediately after first line chemotherapy for relapsed disease. The clinical results of this attempt seem to improve overall survival as compared with conventional therapies, and justify a prospective trial in this specific setting.
EBV-specific CTL therapy is safe and associated with clinical benefit in patients with refractory or metastatic NPC. Sequential combination of CTL therapy with other agents, such as checkpoint inhibitors, could yield optimal results.
Fondazione IRCCS Policlinico San Matteo.
All authors have declared no conflicts of interest.
Current standard-of-care immunotherapies target the interaction between tumor and T cells. However, frequently there are insufficient numbers of tumor-specific T cells present. Hence, these patients may benefit from adoptive cell transfer (ACT) with melanoma-specific T cells. The general conditioning and maintenance treatment for ACT consists of lymphodepleting chemotherapy with or without total body irradiation, and post-transfusion high-dose IL-2. In our hospital we replaced this rather toxic treatment scheme with low-dose interferon-alpha (IFNa).
Twenty-four patients with progressive metastatic melanoma received up to three infusions with ex vivo expanded tumor infiltrating lymphocytes (TIL) every three weeks, ranging between 1-10 x 108 T cells per infusion. One week before the first TIL infusion patients started with daily subcutaneous IFNa injections. These injections were continued for eleven weeks as a maintenance treatment. Total blood count was measured before the start of IFNa, and before each TIL infusion. Furthermore, serum and PBMC were collected at these time-points. Twelve weeks after the first TIL infusion the patients received a radiological response evaluation.
The combination of IFNa and ACT is safe and well tolerated. IFNa causes a mild lymphopenia, neutropenia and leukopenia. Both responders and non-responders show a decrease in these blood counts after one week of IFNa. Strikingly, persistence of leukopenia and in particular neutropenia predicts the response to TIL therapy. Furthermore, high leukocyte/lymphocyte and platelet/lymphocyte ratios are predictive biomarkers for response to treatment. Clinical benefit was seen in 7 out of 24 (29%) patients with stable disease for an average of 36 weeks. Although nineteen patients failed extensive pre-treatment with BRAF/MEK inhibitor and/or anti-PD1 and/or anti-CTLA4, five of them still displayed stabilization of disease (26.3%) after ACT.
The persistence of leukopenia induced by low-dose IFNa is a predictor of response to TIL therapy. Furthermore, this treatment combination is a viable option for heavily pre-treated metastatic melanoma patients.
Local Ethics Committee P04.085.
Medical Oncology, Leiden University Medical Center.
KWF (Dutch Cancer Society).
E.M.E. Verdegaal: In relation to research: Affiliations or financial involvement: ISA pharmaceuticals B.V., AIMM Therapeutics, PamGene. J.B.A.G. Haanen: Advisory boards, consultation and lectures: Pfizer, Bayer, MSD, BMS, Ipsen, Novartis, Roche/Genentech, Neon Therapeutics, Celsius Therapeutics, Gadeta BV, Immunocore. Grants to NKI: BMS, MSD, Novartis, Neon Therapeutics. E. Kapiteijn: Advisory boards: Roche, BMS, MSD, Novarits, Pierre-Fabre, Genzyme-Sanofi, Eisai, Servier, Sirtex, Delcath (for which LUMC received honoraria). Grant support to LUMC: Novartis, BMS. S.H. van der Burg: Advisory boards: ISA Pharmaceuticals B.V., PCI-Biotech, IO-Biotech; Corporate grant support: Innate Pharma, Kite Pharma EU B.V., AIMM Therapeutics; Service agreements: ISA Pharmaceuticals B.B., IO Biotech. All other authors have declared no conflicts of interest.
PSCA, a cell surface protein, is upregulated in many solid tumors & correlates with disease stage. BPX601 is an autologous, T-cell product engineered to contain a PSCA-CD3ξ CAR plus the small molecule rimiducid (Rim)-inducible MyD88/CD40 costimulatory domain. BPX601 is optimized for antigen-directed & independent T cell activation, proliferation & persistence, potentially enhancing efficacy in solid tumors versus traditional CARs. This first-in-human study assesses the safety, biological & clinical activity of BPX601 plus Rim in select PSCA-positive cancers.
NCT02744287 is a 2-part, open-label trial. Part 1 is an ongoing 3 + 3 cell dose escalation to identify the recommended BPX601 cell dose (Day 0) given in combination with a fixed, single Rim dose (0.4 mg/kg; Day 7). Eligibility criteria include previously treated metastatic pancreatic cancer (mPDAC) with measurable disease & positive PSCA expression.
Patients received only cyclophosphamide (CTX) for lymphodepletion (LD) within 3 days before BPX601 infusion. Nine adults have been treated across 3 cell dose levels (cells/kg): 1.25x106 (cells only), 1.25x106+Rim, 2.5x106+Rim. All had mPDAC with ≥2 prior therapies. Common AEs were fatigue & nausea. No DLTs, related SAEs, neurotoxicity or CRS events were reported. Rapid cell engraftment by Day 4 was observed in all patients. No evidence of LD with CTX was seen. Of 6 patients that received Rim: 2 had cell expansion 10- to 20-fold within 7 days; 2 had cell persistence >3 weeks; all had elevated serum cytokines (IP-10, TNFα) correlated with cell expansion. Best response after ≥1 scan was 4 SD ≥ 8 weeks with 2 minor responses (not confirmed; 1 patient had matched CA19-9 decrease) & 2 PD. Disease control without new therapy was 16 & >11 weeks (ongoing) in 1 & 3 patients, respectively.
BPX601 with single-dose Rim was well-tolerated & resulted in enhanced T cell expansion & prolonged persistence in some patients despite lack of LD. Evidence of clinical benefit in this heavily pretreated mPDAC population was seen. Part 2 is planned to open soon & will include CTX/fludarabine LD to maximize engraftment as well as gastric & prostate cancers.
C.R. Becerra: Hhonoraria: Taiho Pharmaceutical; Consulted: SOBI, Ipsen, Takeda, Bayer, Heron, Agenus; Speakers\' bureau: Taiho Pharmaceutical, BMS, Merck Serono, Celgene. S. Paulson: Stock: Immunomedics, Juno, Alexion, Actinium; Consulted: Ipsen, Eisai, AAA, BMS, Merrimack, Taiho; Research funding: Taiho, Eli Lilly, AstraZeneca. G.A. Manji: Consultant: Ardelyx; Research funding: Plexxikon. O. Gardner: Employee of Bellicum Pharmaceuticals. A. Malankar, J. Shaw, D. Blass, B. Ballard, M. Anumula, A. Foster, J. Senesac, P. Woodard: Employee and stock owner: Bellicum Pharmaceuticals. X. Yi: Employee of Bellicum Pharmaceuticals. All other authors have declared no conflicts of interest.
In recent years, antibody-based therapies targeting the Programmed cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) immune checkpoint axis have gained tremendous success in cancer immunotherapy. We embarked on an effort to identify and develop small molecules capable of targeting this immune checkpoint, with an aim to provide new therapeutic options with improved anticancer immune responses, increased tumor penetration, shorter half-life to better managing immune related adverse events, and lower cost of goods.
We developed a number of small molecule inhibitors based on the crystal structure of human PD-1/PD-L1 complex. Active compounds were first identified by an ELISA assay measuring inhibition of the PD-1/PD-L1 interaction, followed by functional cell-based reporter and mixed lymphocyte reaction (MLR) assays. Since these inhibitors specifically block human PD-1/PD-L1 interaction, we co-implanted A375 human melanoma cells along with human peripheral blood mononuclear cells (PBMCs) into immunodeficient NOD/SCID mice to test their efficacy in vivo.
We have obtained potent human PD-1/PD-L1 inhibitors with marked activities in both the cell-based reporter and MLR assays. Moreover, lead compound CCX4503 reduced tumor growth in vivo to a similar extent as the positive control anti-human PD-L1 antibody. Anti-tumor activity was completely dependent on the presence of human PBMCs. The tumor microenvironment analysis indicated that the anti-tumor activity of CCX4503 was accompanied by a significantly higher CD8+ T-Cell/CD4+ T-cell ratio. An X-ray structure of CCX4503 co-crystallized with PD-L1 provided information about the structural basis by which the compound disrupts the PD-1/PD-L1 immune checkpoint interaction.
We have identified and advanced unique small molecule inhibitors of human PD-1/PD-L1 by rational design. Molecules resulting from these efforts, such as CCX4503, exhibited marked inhibition of the PD-1/PD-L1 interaction and signaling in vitro, and also clear anti-tumor effects in an animal model system in vivo.
ChemoCentryx, Inc., Mountain View, CA.
ChemoCentryx, Inc., Mountain View, CA.
M. Vilalta Colomer, S. Li, V. Malathong, C. Lange, D. McMurtrie, J. Yang, H. Roth, J. McMahon, J.J. Campbell, L.S. Ertl, R. Ong, Y. Wang, N. Zhao, S. Yau, T. Dang, P. Zhang, T.J. Schall, R. Singh: Full-time employee of ChemoCentryx. S. Punna: Stock holder: ChemoCentryx.