Author Correction: LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.

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Durable Response to Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, and Prednisone (BV-CHP) in a Patient with CD30-Positive PTCL Arising as a Post-Transplant Lymphoproliferative Disorder (PTLD)

Current Oncology ◽

10.3390/curroncol28060426 ◽

2021 ◽

Vol 28 (6) ◽

pp. 5067-5072

Author(s):

Jennifer Hong ◽

William T. Johnson ◽

Saritha Kartan ◽

Anitha S. Gonsalves ◽

Jonathan M. Fenkel ◽

...

Keyword(s):

T Cell ◽

Poor Prognosis ◽

Lymphoproliferative Disorder ◽

Progression Free Survival ◽

Brentuximab Vedotin ◽

Added Value ◽

Front Line ◽

Durable Response ◽

Free Survival ◽

Prospective Trials

T-cell PTLDs are lymphoid proliferations that develop in recipients of SOT or allogeneic HSCT. They carry an extremely poor prognosis with a reported median survival of only 6 months. The infrequency with which they are encountered makes treatment a challenge due to the lack of prospective trials to guide management. The significantly higher risk of morbidity and mortality in T-cell PTLD, compared to B-cell PTLD, underscores the challenge of treating these patients and the need for new therapeutic options. Brentuximab vedotin, an ADC targeting CD30, is FDA-approved in combination with CHP as front-line treatment for patients with CD30 expressing PTCL. Herein we report a case of CD30-positive T-cell PTLD that was successfully treated with BV-CHP, suggesting the added value of the addition of BV to chemotherapy, contributing to our patient’s long and ongoing progression-free survival. To our knowledge, this is the first documented case of successful treatment using BV-CHP for a CD30-positive, EBV-negative, late T-cell PTLD.

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Prognostic Factors and Biomarkers of Responses to Immune Checkpoint Inhibitors in Lung Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20194931 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4931 ◽

Cited By ~ 13

Author(s):

Andrea Bianco ◽

Fabio Perrotta ◽

Giusi Barra ◽

Umberto Malapelle ◽

Danilo Rocco ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

Cancer Treatment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

T Cell Subsets ◽

Durable Response ◽

Lung Cancer Treatment ◽

The Impact

Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses.

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Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma

Blood Advances ◽

10.1182/bloodadvances.2020002394 ◽

2020 ◽

Vol 4 (19) ◽

pp. 4898-4911 ◽

Cited By ~ 2

Author(s):

Frederick L. Locke ◽

John M. Rossi ◽

Sattva S. Neelapu ◽

Caron A. Jacobson ◽

David B. Miklos ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Tumor Burden ◽

Durable Response ◽

T Cell Therapy ◽

Car T Cell ◽

Large B Cell Lymphoma ◽

Car T Cell Therapy ◽

Car T

Abstract ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

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Durable Response to Sintilimab and Chidamide in a Patient With Pegaspargase- and Immunotherapy-Resistant NK/T-Cell Lymphoma: Case Report and Literature Review

Frontiers in Oncology ◽

10.3389/fonc.2020.608304 ◽

2020 ◽

Vol 10 ◽

Author(s):

Zheng Yan ◽

Shuna Yao ◽

Yanyan Liu ◽

Jianbo Zhang ◽

Peng Li ◽

...

Keyword(s):

T Cell ◽

Hdac Inhibitor ◽

Cell Lymphoma ◽

Combined Treatment ◽

T Cell Lymphoma ◽

Molecular Response ◽

Short Treatment ◽

Durable Response ◽

Median Response ◽

Nk T Cell

The prognosis of patients with relapsed/refractory NK/T-cell lymphoma (NKTCL) is dismal. Immunotherapy has showed encouraging anti-tumor activity in patients with asparaginase-resistant NKTCL; however, only a portion of patients benefit and the median response duration is rather short. Treatment strategies have not been identified for immunotherapy-resistant NKTCL. We describe a patient with primary cutaneous NKTCL experienced disease progression after pegaspargase-based chemotherapy and PD-1 inhibitor (sintilimab)-based immunotherapy. Following a combined treatment of sintilimab and the HDAC inhibitor chidamide, the patient achieved a durable complete molecular response with mild toxicity. This case indicates that the combination of PD-1 inhibitor and HDAC inhibitor might be a treatment choice for immunotherapy-resistant NKTCL.

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90. Fecal Microbiota Transplantation in Metastatic Melanoma Patients Resistant to Anti-PD-1 Treatment

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.014 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S7-S7 ◽

Cited By ~ 2

Author(s):

Ilan Youngster ◽

Erez Baruch ◽

Lior Katz ◽

Adi Lahat ◽

Tal Brosh-Nissimov ◽

...

Keyword(s):

T Cell ◽

Gut Microbiota ◽

Metastatic Melanoma ◽

Cell Activity ◽

Complete Response ◽

Fecal Microbiota ◽

Post Treatment ◽

Response To Treatment ◽

Durable Response ◽

Melanoma Patients

Abstract Background Most metastatic melanoma patients treated with Programed cell Death (PD)-1 blockers fail to achieve a durable response. The gut microbiota profoundly affects host immunity, and fecal microbiota transplantations (FMT) have been shown to enhance anti-PD-1 effectiveness in murine models. We report initial safety and efficacy results from the first patients treated in a Phase I study of FMT and re-induction anti-PD-1 therapy in anti-PD-1 refractory metastatic melanoma. Methods FMT donors were two metastatic melanoma patients who achieved a durable complete response to treatment. FMT recipients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. FMT was conducted by both colonoscopic and oral administration, followed by anti-PD-1 re-treatment. Each recipient underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging. Results Five patients with treatment-resistant metastatic melanoma were recruited. No FMT-related or immunotherapy-related adverse events were observed. To assess engraftment of the new microbiota, recipients were paired with their respective donors and stool 16S rDNA gene sequence analysis was performed. Sequencing results demonstrated post-FMT compositional dissimilarity (Unweighted UniFrac, P = 0.04, FDR q = 0.22) between the two recipient–donor groups. Specific taxonomic dynamics included post-FMT increased abundance of Paraprevotellaceae, previously associated in descriptive studies with responsiveness to treatment, and significant reductions in abundance of β-proteobacteria, previously associated with reduced response to treatment. Immunohistochemical stains of biopsies demonstrated an increased post-FMT infiltration of antigen presenting cells (CD68+) in the gut (paired T-test, P = 0.008) and in the tumor (P = 0.0076). Post-treatment intra-tumoral CD8+ T-cell infiltration was also increased. Three patients had a partial or complete response to treatment post-FMT. Conclusion FMT in metastatic melanoma patients seems to be safe and may alter recipient gut microbiota to resemble that of a responder donor. This alteration may result in intra-tumoral T-cell activity, and conferred clinical and radiological benefit in several recipients previously unresponsive to treatment. Disclosures All Authors: No reported Disclosures.

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BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling

10.1101/669812 ◽

2019 ◽

Cited By ~ 3

Author(s):

Xiaozheng Xu ◽

Amitkumar Fulzele ◽

Yunlong Zhao ◽

Zijun Wu ◽

Yanyan Hu ◽

...

Keyword(s):

T Cell ◽

Cell Signaling ◽

Cell Activity ◽

Immune Checkpoints ◽

Clinical Activity ◽

T Cell Signaling ◽

Tcr Signaling ◽

Durable Response ◽

Infected Cells ◽

Cell Death Protein

ABSTRACTT cell-mediated destruction of tumors and virus-infected cells is restricted by co-inhibitory receptors such as programmed cell death protein 1 (PD-1). Monoclonal antibodies blocking PD-1 have produced impressive clinical activity against human cancers, but durable response is limited to a minority of patients. Previous results suggest that B and T lymphocyte attenuator (BTLA), a co-inhibitory receptor structurally related to PD-1, may contribute to the resistance to PD-1 targeted therapy and co-blockade of BTLA can enhance the efficacy of anti-PD-1 immunotherapy. However, the biochemical mechanism by which BTLA represses T cell activity and to what extent the mechanism differs from that of PD-1 is unknown. Here we examine differences in the ability of BTLA and PD-1 to recruit effector molecules and regulate T cell signaling. We show that PD-1 and BTLA recruit different tyrosine phosphatases to regulate either CD28 or T cell antigen receptor (TCR)-signaling cascades. Our data reveal unexpected disparities between two structurally related immune checkpoints and two phosphatase paralogs.

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Single-cell antigen-specific activation landscape of CAR T infusion product identifies determinants of CD19 positive relapse in patients with ALL

10.1101/2021.04.15.440005 ◽

2021 ◽

Author(s):

Zhiliang Bai ◽

Steven Woodhouse ◽

Dongjoo Kim ◽

Stefan Lundh ◽

Hongxing Sun ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Single Cell ◽

Molecular Mechanisms ◽

T Cell Subsets ◽

Durable Response ◽

Car T Cells ◽

Number Of Patients ◽

Car T

Chimeric antigen receptor modified (CAR) T cells targeting CD19 have mediated dramatic responses in relapsed or refractory acute lymphoblastic leukemia (ALL), yet a notable number of patients have CD19-positive relapse within one year of treatment. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes prior to treatment. Herein we present 101,326 single cell transcriptomes and surface protein landscape from the CAR T infusion products of 12 pediatric ALL patients upon CAR antigen-specific stimulation in comparison with TCR mediated activation and controls. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of Th2 function was associated with CD19 positive relapsed patients (median remission 9.6 months) compared with very durable responders (remission over 54 months). Proteomic profiles also revealed that the frequency of early memory T cell subsets, rather than activation or co-inhibitory signatures could distinguish CD19-positive relapse. Additionally, a deficit of type 1 helper and cytotoxic effector function and an enrichment for terminally differentiated CD8+ T cells exhibiting low cytokine polyfunctionality was associated with initial non-responders. By contrast, the single-cell transcriptomic data of unstimulated or TCR-activated CAR T cells failed to predict clinical responses. In aggregate, our results dissect the landscape of CAR-specific activation states in infusion products that can identify patients who do not develop a durable response to the therapy, and unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long term remission.

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Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma

Cancers ◽

10.3390/cancers12113374 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3374

Author(s):

Elena Shklovskaya ◽

Jenny H Lee ◽

Su Yin Lim ◽

Ashleigh Stewart ◽

Bernadette Pedersen ◽

...

Keyword(s):

T Cell ◽

Cytotoxic T Lymphocyte ◽

Myeloid Cell ◽

Combination Immunotherapy ◽

First Line ◽

Class I Mhc ◽

Durable Response ◽

Mhc I ◽

Quantitative Score ◽

Selection Of

Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the expense of higher toxicity. Currently, there are no robust molecular biomarkers for the selection of first-line immunotherapy. We used flow cytometry to profile pretreatment tumor biopsies from 36 melanoma patients treated with anti-PD-1 or combination (anti-PD-1 plus anti-CTLA-4) immunotherapy. A novel quantitative score was developed to determine the tumor cell expression of antigen-presenting MHC class I (MHC-I) molecules, and to correlate expression data with treatment response. Melanoma MHC-I expression was intact in all tumors derived from patients who demonstrated durable response to anti-PD-1 monotherapy. In contrast, melanoma MHC-I expression was low in 67% of tumors derived from patients with durable response to combination immunotherapy. Compared to MHC-I high tumors, MHC-I low tumors displayed reduced T-cell infiltration and a myeloid cell-enriched microenvironment. Our data emphasize the importance of robust MHC-I expression for anti-PD-1 monotherapy response and provide a rationale for the selection of combination immunotherapy as the first-line treatment in MHC-I low melanoma.

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CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.7513 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 7513-7513 ◽

Cited By ~ 16

Author(s):

Jeremy S. Abramson ◽

Maria Lia Palomba ◽

Leo I. Gordon ◽

Matthew Alexander Lunning ◽

Jon E. Arnason ◽

...

Keyword(s):

T Cell ◽

Phase 1 ◽

Median Number ◽

Tumor Biopsy ◽

Durable Response ◽

Tumor Immune Evasion ◽

Cell Product ◽

Car T Cell ◽

Car T ◽

Heavily Pretreated

7513 Background: JCAR017 is a second-generation, CD19-directed, 4-1BB CAR T cell product comprising CD8 and CD4 CAR T cells in a 1:1 ratio. A multicenter phase 1 trial of JCAR017 in R/R B-cell NHL (NCT02631044) is underway. Methods: Patients with R/R DLBCL, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. There was no minimum ALC requirement for apheresis; no test expansion was required. Treatment includes lymphodepletion with fludarabine and cyclophosphamide, followed by JCAR017. Multiple dose levels (DLs)/administration schedules of JCAR017 are being evaluated. Study objectives include safety, PK, and antitumor response. Results: As of November 23, 2016, 28 patients have been treated and are evaluable for safety and efficacy. Nineteen were male, 9 female; 25 DLBCL, 2 MCL, and 1 FL grade 3B. Median age was 63 years (range 37-79), median number of prior therapies was 4 (range 1-8), 23 (82%) were refractory to their last chemotherapy, and 16 (57%) had prior transplant. No severe cytokine release syndrome (sCRS) was observed; 10 patients had grade 1-2 CRS (1 received tocilizumab). Five patients developed neurotoxicity, including 4 grade 3-4; all events resolved in the 4 patients who had adequate follow up. Median onset of CRS and neurotoxicity were 5 and 11 days, respectively. Four deaths after disease progression occurred, none related to JCAR017. In 20 patients treated at DL1 (5×107 cells), the RR was 80% with 60% achieving CR. One patient with secondary CNS involvement achieved CR without neurotoxicity. JCAR017 was detected at 3 and 6 months in responding patients, including some who relapsed; higher mean peak levels were detected in patients with durable response at 3 months. Data on patients treated at DL2 (1×108 cells), alternative dose schedules, tumor biopsy, and additional biomarkers will be presented. Conclusions: Treatment with JCAR017 results in high CR rate in patients with heavily pretreated R/R DLBCL. Relapses can occur despite persistence of JCAR017, suggesting tumor immune evasion mechanisms may contribute to relapse. Observed toxicities are manageable and occurred at rates lower than those reported for other CD19-directed CAR T cell products. Clinical trial information: NCT02631044.

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