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1. Modeling T cell temporal response to cancer immunotherapy rationalizes development of combinatorial treatment protocols

Author

Barboy, Oren, Bercovich, Akhiad, Li, Hanjie, Eyal-Lubling, Yaniv, Yalin, Adam, Shapir Itai, Yuval, Abadie, Kathleen, Zada, Mor, David, Eyal, Shlomi-Loubaton, Shir, Katzenelenbogen, Yonatan, Jaitin, Diego Adhemar, Gur, Chamutal, Yofe, Ido, Feferman, Tali, Cohen, Merav, Dahan, Rony, Newell, Evan W., Lifshitz, Aviezer, Tanay, Amos, and Amit, Ido

Published
2024
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2. The transcriptional and regulatory identity of erythropoietin producing cells

Author

Kragesteen, Bjørt K., Giladi, Amir, David, Eyal, Halevi, Shahar, Geirsdóttir, Laufey, Lempke, Olga M., Li, Baoguo, Bapst, Andreas M., Xie, Ken, Katzenelenbogen, Yonatan, Dahl, Sophie L., Sheban, Fadi, Gurevich-Shapiro, Anna, Zada, Mor, Phan, Truong San, Avellino, Roberto, Wang, Shuang-Yin, Barboy, Oren, Shlomi-Loubaton, Shir, Winning, Sandra, Markwerth, Philipp P., Dekalo, Snir, Keren-Shaul, Hadas, Kedmi, Merav, Sikora, Martin, Fandrey, Joachim, Korneliussen, Thorfinn S., Prchal, Josef T., Rosenzweig, Barak, Yutkin, Vladimir, Racimo, Fernando, Willerslev, Eske, Gur, Chamutal, Wenger, Roland H., and Amit, Ido

Published
2023
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4. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing

Author

Cohen, Yael C., Zada, Mor, Wang, Shuang-Yin, Bornstein, Chamutal, David, Eyal, Moshe, Adi, Li, Baoguo, Shlomi-Loubaton, Shir, Gatt, Moshe E., Gur, Chamutal, Lavi, Noa, Ganzel, Chezi, Luttwak, Efrat, Chubar, Evgeni, Rouvio, Ory, Vaxman, Iuliana, and Pasvolsky, Oren

Subjects
Oncology, Experimental, Molecular dynamics -- Research, Drug resistance -- Research, Multiple myeloma -- Drug therapy -- Patient outcomes, Cancer -- Relapse -- Research, Biological sciences, Health
Abstract

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors. Integration of longitudinal single-cell analysis of relapsed and refractory multiple myeloma patients in a prospective clinical trial uncovers new pathways of drug resistance and identifies potential actionable targets., Author(s): Yael C. Cohen [sup.1] [sup.2] , Mor Zada [sup.1] [sup.3] , Shuang-Yin Wang [sup.3] , Chamutal Bornstein [sup.3] , Eyal David [sup.3] , Adi Moshe [sup.3] , Baoguo Li [...]

Published
2021
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6. Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Author

Ledergor, Guy, Weiner, Assaf, Zada, Mor, Wang, Shuang-Yin, Cohen, Yael C., Gatt, Moshe E., Snir, Nimrod, Magen, Hila, Koren-Michowitz, Maya, Herzog-Tzarfati, Katrin, Keren-Shaul, Hadas, Bornstein, Chamutal, Rotkopf, Ron, Yofe, Ido, David, Eyal, Yellapantula, Venkata, Kay, Sigalit, Salai, Moshe, Ben Yehuda, Dina, Nagler, Arnon, Shvidel, Lev, Orr-Urtreger, Avi, Halpern, Keren Bahar, Itzkovitz, Shalev, Landgren, Ola, San-Miguel, Jesus, Paiva, Bruno, Keats, Jonathan J., Papaemmanuil, Elli, Avivi, Irit, Barbash, Gabriel I., Tanay, Amos, and Amit, Ido

Published
2018
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8. The transcriptional and regulatory identity of erythropoietin producing cells

Author

Kragesteen, Bjørt K, Giladi, Amir, David, Eyal, Halevi, Shahar, Geirsdóttir, Laufey, Lempke, Olga M, Li, Baoguo, Bapst, Andreas M, Xie, Ken, Katzenelenbogen, Yonatan, Dahl, Sophie L, Sheban, Fadi, Gurevich-Shapiro, Anna, Zada, Mor, Phan, Truong San, Avellino, Roberto, Wang, Shuang-Yin, Barboy, Oren, Shlomi-Loubaton, Shir, Winning, Sandra, Markwerth, Philipp P, Dekalo, Snir, Keren-Shaul, Hadas, Kedmi, Merav, Sikora, Martin, Fandrey, Joachim, Korneliussen, Thorfinn S, Prchal, Josef T, Rosenzweig, Barak, Yutkin, Vladimir, et al, University of Zurich, and Kragesteen, Bjørt K

Subjects
1300 General Biochemistry, Genetics and Molecular Biology, General Biochemistry, 570 Life sciences, biology, 610 Medicine & health, Genetics and Molecular Biology, General Medicine, 10052 Institute of Physiology
Published
2023

10. Daratumumab Carfilzomib Lenalidomide Dexamethasone Provides Effective Salvage for Functionally and Cytogenetically High-Risk Myeloma Patients, Except Those Expressing Module-1 Transcriptional Signature: Extended Follow-up from Kydar Multicenter Clinical/Translational Trial.

Author

Cohen, Yael C, primary, Gatt, Moshe E, additional, Luttwak, Efrat, additional, Lavi, Noa, additional, Ganzel, Chezi, additional, Chubar, Evgeni, additional, Rouvio, Ory, additional, Vaxman, Iuliana, additional, Pasvolsky, Oren, additional, Ballan, Mouna, additional, Tadmor, Tamar, additional, Nemets, Anatoly, additional, Jarchowsky, Osnat, additional, Shvetz, Olga, additional, Shpilberg, Ofer, additional, Dally, Najib, additional, Leiba, Merav, additional, Weiner, Assaf, additional, Zada, Mor, additional, Wang, Shuang-Yin, additional, Gur, Chamutal, additional, Lowenton-Spier, Noa, additional, Goor-Porges, Liron, additional, Amit, Ido, additional, and Avivi, Irit, additional

Published
2022
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12. LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma

Author

Gur, Chamutal, primary, Wang, Shuang-Yin, additional, Sheban, Fadi, additional, Zada, Mor, additional, Li, Baoguo, additional, Kharouf, Fadi, additional, Peleg, Hagit, additional, Aamar, Suhail, additional, Yalin, Adam, additional, Kirschenbaum, Daniel, additional, Braun-Moscovici, Yolanda, additional, Jaitin, Diego Adhemar, additional, meir-salame, Tomer, additional, Hagai, Efrat, additional, Kragesteen, Bjørt K., additional, Avni, Batia, additional, Grisariu, Sigal, additional, Bornstein, Chamutal, additional, Shlomi-Loubaton, Shir, additional, David, Eyal, additional, Shreberk-Hassidim, Rony, additional, Molho-Pessach, Vered, additional, Amar, Dalit, additional, Tzur, Tomer, additional, Kuint, Rottem, additional, Gross, Moshe, additional, Barboy, Oren, additional, Moshe, Adi, additional, Fellus-Alyagor, Liat, additional, Hirsch, Dana, additional, Addadi, Yoseph, additional, Erenfeld, Shlomit, additional, Biton, Moshe, additional, Tzemach, Tehila, additional, Elazary, Anat, additional, Naparstek, Yaakov, additional, Tzemach, Reut, additional, Weiner, Assaf, additional, Giladi, Amir, additional, Balbir-Gurman, Alexandra, additional, and Amit, Ido, additional

Published
2022
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13. Single Cell RNA Sequencing in Patients Enrolled in a Selinexor Clinical Trial Reveals Overexpression of Alternative Nuclear Export Pathways Associated with Resistance to Selinexor in Refractory Multiple Myeloma

Author

Cohen, Yael C, primary, Zada, Mor, additional, Wang, Shuang-Yin, additional, Bentur, Ohad S., additional, Chubar, Evgeni, additional, Cohen, Amos, additional, Lavi, Noa, additional, Magen, Hila, additional, Gatt, Moshe, additional, Zektser, Miri, additional, Leiba, Merav, additional, Stemer, Galia, additional, Shragai, Tamir, additional, Avivi, Irit, additional, Weiner, Assaf, additional, and Amit, Ido, additional

Published
2021
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15. A Novel Therapy-Resistance Transcriptional Signature Based on Single Cell Analysis in Kydar Clinical Trial

Author

Cohen, Yael C, primary, Zada, Mor, additional, Wang, Shuang-Yin, additional, Bornstein, Chamutal, additional, David, Eyal, additional, Moshe, Adi, additional, Li, Baoguo, additional, Shlomi, Shir, additional, Gatt, Moshe, additional, Lavi, Noa, additional, Ganzel, Chezi, additional, Lutwak, Efrat, additional, Rouvio, Ory, additional, Vaxman, Iuliana, additional, Pasvolsky, Oren, additional, Ballan, Mouna, additional, Tadmor, Tamar, additional, Nemets, Anatoly, additional, Jarchowcky Dolberg, Osnat, additional, Chober, Yevgeny, additional, Shvetz, Olga, additional, Leiba, Merav, additional, Shpilberg, Ofer, additional, Deli, Nagib, additional, Avivi, Irit, additional, Weiner, Assaf, additional, and Amit, Ido, additional

Published
2020
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16. Kydar Multicenter Trial of Quadruple Regimen for Induction Resistant Myeloma Combined with Translational Single-Cell Analysis Identifies Potential Drivers of Advanced Resistance, Including Novel Immune Checkpoints

Author

Cohen, Yael C, primary, Zada, Mor, primary, Gatt, Moshe E., primary, Lavi, Noa, primary, Ganzel, Chezi, primary, Wang, Shuang-Yin, primary, Weiner, Assaf, primary, Ledergor, Guy, primary, Chubar, Evgeni, primary, Rouvio, Ory, primary, Vaxman, Iuliana, primary, Ballan, Mouna, primary, Tadmor, Tamar, primary, Nemets, Anatoly, primary, Jarchowcky Dolberg, Osnat, primary, Shvetz, Olga, primary, Shpilberg, Ofer, primary, Deli, Nagib, primary, Avivi, Irit, primary, and Amit, Ido, primary

Published
2019
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17. Lung Single-Cell Signaling Interaction Map Reveals Basophil Role in Macrophage Imprinting

Author

Cohen, Merav, primary, Giladi, Amir, additional, Gorki, Anna-Dorothea, additional, Solodkin, Dikla Gelbard, additional, Zada, Mor, additional, Hladik, Anastasiya, additional, Miklosi, Andras, additional, Salame, Tomer-Meir, additional, Halpern, Keren Bahar, additional, David, Eyal, additional, Itzkovitz, Shalev, additional, Harkany, Tibor, additional, Knapp, Sylvia, additional, and Amit, Ido, additional

Published
2018
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19. Single cell analysis of multiple myeloma.

Author

Ledergor, Guy, primary, Weiner, Assaf, additional, Zada, Mor, additional, Cohen, Yael Chava, additional, Gatt, Moshe E, additional, Snir, Nimrod, additional, Magen, Hila, additional, Koren-Michowitz, Maya, additional, Keren-Shaul, Hadas, additional, Yellapantula, Venkata, additional, Paiva, Bruno, additional, Nagler, Arnon, additional, San-Miguel, Jesus, additional, Ben-Yehuda, Dina, additional, Papaemmanuil, Elli, additional, Avivi, Irit, additional, Barbash, Gabriel I, additional, Tanay, Amos, additional, and Amit, Ido, additional

Published
2018
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24. Determinants of Response to Anti CD-19 CAR-T Cells for Diffuse Large B-Cell Lymphoma in Pre-Treatment Peripheral Blood Mononuclear Cells Using Single-Cell RNA-Seq

Author

Ram, Ron, Katzenelenbogen, Yonatan, Gurevich Shapiro, Anna, Winter, Eitan, Barboy, Oren, Zada, Mor, Halevi, Shahar, David, Eyal, Avivi Mazza, Irit, and Amit, Ido

Abstract

Background:Chimeric antigen receptor T (CAR-T) cell therapy has become the standard of care in patients with relapsed/refractory diffuse large cell lymphoma (R/R DLBCL), providing durable remission in 40% of patients. Lack of response is likely to be attributed to inter- and intra-patient variability, including PBMC heterogeneity and apheresis material composition, CAR-T infusion product, in-vivo expansion and activity of CAR-T cells and the development of tumor-intrinsic mechanisms. Current methods for evaluating CAR-T cell activation and potency have limited predictive value for clinical outcomes. To address this challenge, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) obtained from patients with R/R LBCL patients at the time of apheresis for the manufacturing of anti-CD19 CAR-T cell therapy. Methods: Between 10/2020 and 03/2022, 31 patients who underwent lymphopheresis were enrolled. Samples were obtained - 1) At day of lymphopheresis from peripheral blood; 2) On the day of infusion of CAR-T from the product; and 3) On day +7 after infusion from peripheral blood. All patients had day +30 PET-CT. In addition, PBMCs samples from healthy donors were used as control to analyze baseline characteristics compared to the DLBCL patients. PBMCs from patients of healthy donors were purified from frozen blood samples by density gradient separation, stained using human CD45 antibody and loaded onto a 10x Chromium system. libraries were generated using the 10X Genomics Chromium Single Cell 3' Kit. The data was processed and analyzed using the Seurat R package. The study was approved by the local Ethic committee. Results:Patient characteristics: 31 RR DLBCL patients (42% females; median age 72, range 47-81 years), all treated with CAR-T cells therapy as third line of therapy, participated in the study. All patients underwent lymphopheresis, followed by CAR-T production. Disease status at lymphodepletion was complete remission (CR, n=4, 13%), partial remission (n=6, 19%), and progressive disease (n=21, 68%) and patients received either tisagenlecleucel (n=20, 65%) or axicabtagene ciloleucel (n=11, 35%) . PET scan performed on day 30 post treatment revealed that 68% and 32% obtained CR, and PD, respectively. scRNA analysis revealed differences in PBMC composition between healthy donors and LBCL patients (Figure 1A), with lower levels of naïve and memory T cells and elevated levels of activated monocytes in LBCL patients, suggesting a shift towards an inflamed and pre-dysfunctional immune state. Categorization of LBCL patients into responders (PR/CR on day +30 PET-CT) and non-responders (PD on day +30 PET-CT) revealed differences in immune cell subsets between responders and non-responders (Figure 2A), with enriched inflammation-related pathways in non-responders, In contrast, responders exhibited a distinct healthy-like immune profiles, particularly high levels of naive T cells, similar to that obtained in their age matched healthy controls. Of note, non-responders showed alterations in immune cell subsets, including increased levels of T regulatory cells and effector NK cells. Furthermore, non-responders demonstrated a prominent inflammatory immune profile, characterized by gene pathways related to inflammation and activation, such as type I and III IFN-G, and TNFb response (Figure 1B). Notably, an IFN-G score was significantly higher in non-responder's monocytes subpopulations, compared to responders. Conclusions:These findings indicate that the success of CAR-T therapy could be determined by the molecular characteristics and subpopulation distribution of each patient's PBMC. The diverse immune profiles of DLBCL patients might impact the effectiveness of their immune cells in generating successful CAR-T products or providing a conducive environment for CAR T cells to combat cancer. Furthermore, these findings emphasize the potential of scRNA-seq in evaluating PBMC from CAR-T patients prior to treatment, allowing the potential calculation of an “immune potency score” associated with the probability of a positive outcome from CAR-T treatment of DLBCL patients. This score could potentially be used by oncologists in decision-making processes to determine the appropriate candidates for CAR-T therapy.

Published
2023
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