Scott S. Tykodi

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

BACKGROUND Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the hosts immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

An antigen produced by splicing of noncontiguous peptides in the reverse order

CD8-positive T lymphocytes recognize peptides that are usually derived from the degradation of cellular proteins and are presented by class I molecules of the major histocompatibility complex. Here we describe a human minor histocompatibility antigen created by a polymorphism in the SP110 nuclear phosphoprotein gene. The antigenic peptide comprises two noncontiguous SP110 peptide segments spliced together in reverse order to that in which they occur in the predicted SP110 protein. The antigenic peptide could be produced in vitro by incubation of precursor peptides with highly purified 20S proteasomes. Cutting and splicing probably occur within the proteasome by transpeptidation.

Allogeneic Hematopoietic Cell Transplantation for Metastatic Renal Cell Carcinoma after Nonmyeloablative Conditioning: Toxicity, Clinical Response, and Immunological Response to Minor Histocompatibility Antigens

Purpose: This phase I trial assessed the safety, efficacy, and immunologic responses to minor histocompatibility antigens following nonmyeloablative allogeneic hematopoietic cell transplantation as treatment for metastatic renal cell carcinoma. Experimental Design: Eight patients received conditioning with fludarabine and low-dose total body irradiation followed by hematopoietic cell transplantation from an HLA-matched sibling donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for donor engraftment of myeloid and lymphoid cells, for clinical response by serial imaging, and for immunologic response by in vitro isolation of donor-derived CD8+ CTLs recognizing recipient minor histocompatibility (H) antigens. Results: All patients achieved initial mixed hematopoietic chimerism with two patients rejecting their graft and recovering host hematopoiesis. Four patients developed acute, grade 2 to 3, graft-versus-host disease and four patients developed extensive chronic graft-versus-host disease. Five patients had progressive disease, two patients had stable disease, and one patient experienced a partial response after receiving donor lymphocyte infusions and IFN-α. CD8+ CTL clones recognizing minor H antigens were isolated from five patients studied. Clones from three patients with a partial response or stable disease recognized antigens expressed on renal cell carcinoma tumor cells. Conclusions: Treatment of metastatic renal cell carcinoma with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning with fludarabine/total body irradiation is feasible and may induce tumor regression or stabilization in some patients. CD8+ CTL-recognizing minor H antigens on tumor cells can be isolated posttransplant and could contribute to the graft-versus-tumor effect. Such antigens may represent therapeutic targets for posttransplant vaccination or adoptive T-cell therapy to augment the antitumor effects of allogeneic hematopoietic cell transplantation.

Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression: A Subgroup Analysis of a Randomized Clinical Trial

IMPORTANCE Response patterns with immunotherapy may differ from those of other treatments. This warrants further investigation because some patients may benefit from continued immunotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined first progression. OBJECTIVE To evaluate the safety and potential benefit of treatment with nivolumab, a programmed cell death 1 immune checkpoint inhibitor, beyond investigator-assessed first progression in patients with metastatic renal cell carcinoma (mRCC). DESIGN, SETTING, AND PARTICIPANTS Subgroup analysis of a blinded, randomized, multicenter, phase 2 dose-ranging trial initiated May 31, 2011, including patients with clear-cell mRCC previously treated with antiangiogenic therapy. Data cutoffs for this subgroup analysis were May 15, 2013, for progression-free survival and objective response rate and March 5, 2014, for overall survival and duration of response. In this analysis, patients treated beyond first progression received their last dose of nivolumab more than 6 weeks after RECIST-defined progression, and patients not treated beyond first progression discontinued nivolumab before or at RECIST-defined progression. INTERVENTIONS Nivolumab 0.3, 2, or 10 mg/kg intravenously every 3 weeks. MAIN OUTCOMES AND MEASURES Safety and efficacy of nivolumab treatment. RESULTS Of 168 patients (median [range] age, 61 [37-81] years; 72% male) randomized to nivolumab, 154 experienced progression (36 were treated beyond first progression, 26 were treated beyond first progression for ≤6 weeks, and 92 were not treated beyond first progression), 13 were treated and did not experience progression, and 1 was not treated. Prior to first progression, the RECIST-defined objective response rate was 14% (5 patients) and 16% (15 patients), and median progression-free survival was 4.2 (95% CI, 2.8-5.5) and 2.6 (95% CI, 1.5-3.9) months in patients treated and not treated beyond progression, respectively. Following initial progression, 25 (69%) patients treated beyond progression experienced subsequent tumor reduction or stabilization in target lesion size. The incidence of treatment-related adverse events was higher in patients treated beyond progression (n = 29 [81%]) vs those not treated beyond progression (n = 61 [66%]); however, after adjusting for length of treatment exposure, incidence was lower in patients treated beyond progression (322.9 vs 518.7 incidence rate/100 patient-years for patients treated vs not treated beyond progression). CONCLUSIONS AND RELEVANCE In this subgroup analysis, a proportion of patients who continued treatment beyond RECIST-defined first progression demonstrated sustained reductions in tumor burden or stabilization in the size of target lesions, with an acceptable safety profile. Further analysis will help define the clinical benefit for patients with mRCC treated with nivolumab beyond progression. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01354431.

C19orf48 encodes a minor histocompatibility antigen recognized by CD8+ cytotoxic T cells from renal cell carcinoma patients.

Purpose: Tumor regression has been observed in some patients with metastatic renal cell carcinoma (RCC) after nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Cellular and molecular characterization of antigens recognized by tumor-reactive T cells isolated from responding patients could potentially provide insight into the mechanisms of tumor regression. Experimental Design: CD8+ CTL clones that recognized a novel RCC-associated minor histocompatibility (H) antigen presented by HLA-A*0201 were isolated from two patients with metastatic RCC who experienced tumor regression or stable disease following nonmyeloablative allogeneic HCT. These clones were used to screen a cDNA library and isolate the unique cDNA encoding the antigen. Results: An alternative open reading frame in the C19orf48 gene located on chromosome 19q13 encodes the HLA-A*0201–restricted minor H antigen recognized by the RCC-reactive T cells. The differential T-cell recognition of donor- and recipient-derived target cells is attributable to a nonsynonymous single-nucleotide polymorphism within the nucleotide interval that encodes the antigenic peptide. Assays for gene expression and CTL recognition showed that the C19orf48-encoded peptide is widely expressed in renal tumors and solid tumors of other histologies. The antigenic peptide can be processed for CTL recognition via both TAP-dependent and TAP-independent pathways. Conclusions: Donor T-cell responses against the HLA-A*0201–restricted minor H antigen encoded by C19orf48 may contribute to RCC regression after MHC-matched allogeneic HCT.

CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma

BACKGROUND The randomized, phase 3 CheckMate 025 study of nivolumab (n=410) versus everolimus (n=411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). OBJECTIVE To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. DESIGN, SETTING, AND PARTICIPANTS Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. INTERVENTION Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. RESULTS AND LIMITATIONS The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and ≥65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48, 95% confidence interval 0.32-0.70). The mortality rate at 12 mo for all subgroups was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab. Limitations include the post hoc analysis and differing sample sizes between groups. CONCLUSION The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. PATIENT SUMMARY We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.

PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence

Renal cell carcinoma (RCC) is the most common primary malignant tumor of the kidney in adults, representing approximately 4% of all adult cancers in the United States. Metastatic RCC is poorly responsive to conventional cytotoxic chemotherapies but can be sensitive to T-cell-directed immunotherapies such as interferon-α or interleukin-2. Despite recent progress in the application of antiangiogenic “targeted therapies” for metastatic RCC, high-dose interleukin-2 remains an appropriate first-line therapy for select patients and is associated with durable complete remissions in a small fraction of treated patients. Thus, advanced RCC provides a unique opportunity to investigate the requirements for effective antitumor immunotherapy. Accumulating evidence suggests that resistance mechanisms exploited by RCC and other tumor types may play a dominant role in limiting the effectiveness of tumor-reactive adaptive immune responses. Expression of the inhibitory coreceptor programmed cell death-1 (PD-1) on tumor-infiltrating lymphocytes within RCC tumors, as well as the expression of the PD-1 ligand (PD-L1) on RCC tumor cells, are strong negative prognostic markers for disease-specific death in RCC patients. Monoclonal antibodies targeting either PD-1 or PD-L1 have now entered clinic trials and have demonstrated promising antitumor effects for refractory metastatic RCC. This review summarizes the results of published and reported studies of PD-1- and PD-L1-targeted therapies enrolling patients with advanced RCC, focusing on key safety, toxicity, and efficacy end points. Prospects for advanced phase clinical testing and novel therapy combinations with PD-1- and PD-L1-targeted agents are discussed.

HLA-F and MHC-I Open Conformers Cooperate in a MHC-I Antigen Cross-Presentation Pathway

Peptides that are presented by MHC class I (MHC-I) are processed from two potential sources, as follows: newly synthesized endogenous proteins for direct presentation on the surface of most nucleated cells and exogenous proteins for cross-presentation typically by professional APCs. In this study, we present data that implicate the nonclassical HLA-F and open conformers of MHC-I expressed on activated cells in a pathway for the presentation of exogenous proteins by MHC-I. This pathway is distinguished from the conventional endogenous pathway by its independence from TAP and tapasin and its sensitivity to inhibitors of lysosomal enzymes, and further distinguished by its dependence on MHC-I allotype-specific epitope recognition for Ag uptake. Thus, our data from in vitro experiments collectively support a previously unrecognized model of Ag cross-presentation mediated by HLA-F and MHC-I open conformers on activated lymphocytes and monocytes, which may significantly contribute to the regulation of immune system functions and the immune defense.

Development of modified vaccinia Ankara-5T4 as specific immunotherapy for advanced human cancer.

Background: The tumor-associated antigen 5T4 is expressed on a high percentage of human carcinomas and has limited expression in normal tissues. A recombinant pox virus vector expressing this antigen, modified vaccinia Ankara (MVA)-5T4, has been tested as a cancer vaccine. Objective: Treatment with MVA-5T4 has been studied both as a single agent and in combination with standard chemo-, biologic- or targeted-therapies in patients with advanced colorectal cancer, renal cell carcinoma (RCC) or hormone-refractory prostate cancer. Methods: This review summarizes data from clinical studies with MVA-5T4 reported in published manuscripts, meeting abstracts or posted on websites relevant to clinical trials or MVA-5T4. Results/conclusion: Vaccination with MVA-5T4 is well tolerated and elicits 5T4-specific humoral and/or cellular responses in most of the treated patients. Retrospective analyses of Phase II studies have suggested a positive association between immune responses to 5T4 and favorable clinical outcomes. A continuing Phase III, double-blind, placebo-controlled trial seeks to confirm a positive association between vaccination with MVA-5T4 and survival in patients with advanced RCC.

T-cell therapy targeting minor histocompatibility Ags for the treatment of leukemia and renal-cell carcinoma

healthsciences The graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactions that occur after MHC-identical allogeneic hematopoietic cell transplantation (HCT) are mediated by T lymphocytes derived from the donor. We have previously shown that CD8 1 cytotoxic T lymphocytes (CTL) specific for minor histocompatibility (H) Ags expressed in recipient hematopoietic cells, including leukemic cells, but not widely expressed in non-hematopoietic tissues, can be isolated from most MHC-identical transplant recipients [1]. These CTL lyse AML and ALL blasts in vitro, and can inhibit the engraftment of human AML stem cells in nonobese diabetic (NOD)/SCID mice [2]. CD8 1 CTL clones specific for tissue-restricted minor H-Ags represent potential therapeutic reagents for adoptive T-cell therapy, designed to selectively enhance the GvL effect without inducing GvHD. A Phase I trial has been initiated at the Fred Hutchinson Cancer Research Center to evaluate the safety and antileukemic efficacy of adoptive T-cell therapy with CD8 1 CTL clones specific for tissue-restricted minor H-Ags, in patients with advanced myelodysplastic syndrome (MDS) and acute leukemia who relapse after HCT from an MHCidentical donor. The CTL clones are generated from transplant recipients prospectively at the time of transplant, and characterized for tissue specificity and Class I MHC restriction. Sequencing of each clone’s uniquely rearranged T-cell receptor b -chain V-D-J region allows the design of PCR assays that facilitate in vivo tracking of adoptively transferred CTL. Upon post-transplant relapse, patients receive cytoreductive chemotherapy, followed by three infusions of minor H-Ag-specific CTL at an escalating dose. If no toxicity is observed, additional CTL infusions are administered at weekly intervals, followed by a 14-day course of low-dose IL-2. In concurrent laboratory studies, cDNA expression cloning is being used to identify the genes encoding the Ags recognized by the CTL clones used in T-cell therapy. Graft-versus-tumor effects are also observed after nonmyeloablative MHC-identical HCT for renal-cell carcinoma (RCC), and studies to investigate the specificity of effector cells involved have recently been initiated [3]. CD8 1 minor H-Ag-specific CTL clones have been isolated from RCC patients after nonmyeloablative HCT. Several CTL clones lyse RCC cell-lines in an MHCrestricted fashion, suggesting that adoptive T-cell therapy targeting minor Ags expressed by RCC cells could be used to enhance the graft-versus-tumor effect after allogeneic HCT for metastatic RCC.