Immune cells called group 3 innate lymphoid cells (ILC3s) play an essential role in establishing tolerance to symbiotic microbes that dwell in the human gastrointestinal tract, according to a study led by researchers at Weill Cornell Medicine.

The discovery, reported Sept. 7 in Nature, illuminates an important aspect of gut health and mucosal immunityone that may hold the key to better treatments for inflammatory bowel disease (IBD), colon cancer and other chronic disorders.

As part of this study, we define a novel pathway that drives immune tolerance to microbiota in the gastrointestinal tract, said senior author Dr. Gregory F. Sonnenberg, associate professor of microbiology and immunology in medicine and head of basic research in the Division of Gastroenterology & Hepatology, and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. This is a fundamental advance in our understanding of mucosal immunity and may hold the key to understanding what goes wrong when the immune system begins to inappropriately attack microbiota in diseases such as IBD.

Drs.Mengze Lyu and Gregory Sonnenberg

Scientists have long known that trillions of bacteria, fungi, and other microbes dwell symbiotically in the intestines of mammals. The mechanism by which the immune system normally tolerates these beneficial gut microbes, instead of attacking them, has not been well understood. But there is evidence that this tolerance breaks down in IBD, leading to harmful flareups of gut inflammation. Thus, a detailed understanding of gut immune tolerance could enable the development of powerful new treatments for IBDa class of diseases that include Crohns disease and ulcerative colitis, which affect several million individuals in the United States alone.

In the study, Dr. Sonnenberg and colleagues, including lead author Dr. Mengze Lyu, a postdoctoral researcher in the Sonnenberg lab, used single-cell sequencing and fluorescent imaging techniques to delineate immune cells in the mesenteric lymph nodes that drain the intestines of healthy mice. They focused on cells expressing a transcription factor, RORt, which are known to drive either inflammation or tolerance in response to microbes that colonize the intestine. The dominant immune cell types in these tissues, they found, were T cells and ILC3s. The latter are a family of immune cells that represent an innate counterpart of T cells, and work as a first line of defense in mucosal tissues such as the intestines and lungs.

In close collaboration with researchers at the University of Birmingham, UK, the scientists observed that in lymph node regions called interfollicular zones, ILC3s are in close association with a specific type of T cell, called RORt+ regulatory T cells (Tregs), which are adapted to dial down inflammation and immune activity to promote tolerance in the gut.

We previously defined key roles for ILC3s in regulating adaptive immunity, but these findings are exciting as they provoke a concept that ILC3s directly interact with Tregs to control immune tolerance in the gut, said Dr. David R. Withers, professor of immune regulation at the Institute of Immunology and Immunotherapy and the University of Birmingham. Dr. Withers and his laboratory are key contributors to this study and long-term collaborators of Dr. Sonnenberg.

The researchers next found evidence that ILC3s play an essential role in promoting the RORt+Treg population in the gut. Much like how immune responses are generated to disease-causing microbes, the ILC3s present pieces of gut-dwelling microbes; but this elicited RORt+ Tregs that specifically recognize these microbes rather than an inflammatory immune response. These RORt+ Tregs then suppress other T cell responses and enforce tolerance to the microbiota.

The scientists found that when they deleted the surface molecule, MHC class II, that ILC3s use to present microbial antigens, thus impeding ILC3s interactions with RORt+ Tregs, the observed RORt+ Tregs were substantially lower than in normal mice, and the affected mice developed spontaneous gut inflammation. At the same time, inflammatory RORt+ T cells, called T helper (Th)17 cells, were dramatically increased in these micein part because many Tregs, bereft of the usual signals from their ILC3 helpers, turned into Th17 cells.

Our extensive research reveals that ILC3s are necessary and sufficient enforcers of immune tolerance to gut microbes, Dr. Lyu said. In addition, we now have a sophisticated understanding of the signals that ILC3s use to communicate with T cells and drive the generation of microbiota-specific Tregs.

To confirm the potential relevance to humans, the researchers analyzed samples of inflamed gut tissue from pediatric IBD patients or healthy individuals in close collaboration with Dr. Robbyn E. Sockolow, professor of clinical pediatrics and chief of the division of Pediatric Gastroenterology, Hepatology and Nutrition in the Department of Pediatrics at Weill Cornell Medicine and a pediatric gastroenterologist at NewYork-Presbyterian Komansky Children's Hospital and Center for Advanced Digestive Care. With Dr. Socklolow and the Roberts Institute Live Cell Bank, they found evidence that communication between ILC3s and RORt+Tregs is disrupted in IBD patients.

Our exciting results provide a potential explanation for why immune tolerance is impaired in IBD patients, which could provoke new therapies with the goal of re-educating the immune system to limit chronic inflammation directed against the microbiota, Dr. Sockolow said.

Dr. Sonnenberg and colleagues now are trying to determine how the ILC3-T cell tolerance mechanism distinguishes between symbiotic, helpful microbes and disease-causing ones. But the results so far suggest, that future cell therapies to restore ILC3 functionality might have powerful effects in suppressing inflammation in IBD. Further, it remains possible that this pathway could be harnessed to limit other inflammatory and autoimmune disorders, as recently demonstrated by the Sonnenberg Lab in mouse models of multiple sclerosis.

The fact that the ILC3s are essential to orchestrate tolerance by promoting antigen-specific Tregs is particularly important, Dr. Sonnenberg notes, for it suggests the possibility of highly targeted treatments that can precisely suppress a source of inappropriate immune activity without compromising immunity as a whole.

Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, R01AI162936 and R01CA274534); an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund; the Meyer Cancer Center Collaborative Research Initiative; The Dalton Family Foundation; the Crohns and Colitis Foundation; and Linda and Glenn Greenberg. Dr. Sonnenberg is a CRI Lloyd J. Old STAR. The JRI IBD Live Cell Bank is supported by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation, the Sanders Family and Weill Cornell Medicine Division of Pediatric Gastroenterology, Hepatology, and Nutrition.

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Discovery Reveals How the Immune System Tolerates Friendly Gut Bacteria - Weill Cornell Medicine Newsroom

A high proportion of myeloid cells may contribute to recurrence in those with long progression-free survival by promoting cancer growth and/or suppressing antitumor immunity.

Treatment with B-cell maturation antigen (BCMA)-targeted T-cell therapy increased the likelihood of longer progression-free survival (PFS) for individuals with myeloma whose tumor immune microenvironment had a more diverse baseline T-cell repertoire, distinct changes to immune cell populations, and fewer markers of immune cell exhaustion, according to the results of a study published in Blood Cancer Discovery.

Two CAR T-cell therapies targeting the [BCMA] are now approved for the treatment of myeloma, but the challenge is that many of the responses to this therapy are not durable, and patients remain at risk for recurrence, Madhav Dhodapkar, MBBS, a professor at the Emory University School of Medicine said in a statement. A key goal in the field is to identify the factors that influence the durability of response so that we can improve treatment accordingly.

In the study, investigators from Emory University and the University of Pennsylvania analyzed 28 pre- and post-treatment bone marrow samples from 11 individuals who had clinical responses to BCMA-targeted CAR T-cell therapy in a previously reported phase 1 clinical trial.

They analyzed samples by single-cell approaches, including CITE-Seq, transcriptomics, mass cytometry, and T-cell receptor sequencing. They compared the change in bone marrow between individuals with long and short PFS, which were defined as greater than 6 months or less than 6 months, respectively.

Investigators found that in individuals with long PFS, the proportion of T cells in bone marrow increased after treatment, while myeloid cell proportions decreased.

They noted that these changes were not observed among individuals with short PFS.

A high proportion of myeloid cells may have contributed to recurrence in the individuals with long PSF by promoting cancer growth and/or suppressing antitumor immunity, the investigators said.

Additionally, post-treatment CAR and non-CAR T cells from individuals with long PFS had a distinct genomic signature with a lower expression of immune checkpoint genes and other genes associated with T-cell exhaustion compared with those with short PFS, according to investigators.

Also, T cells from individuals with long PFS had higher expression of genes associated with bone marrow retention.

Investigators also found that baseline features, such as greater T-cell receptor diversity, higher tumor expression of interferon response genes and mature plasma genes, and lower tumor expression of genes associated with epithelial-to-mesenchymal transition, were associated with PFS.

The major finding of this study is that the durability of response may be dependent on characteristics of non-CAR T cells and other immune cells in the tumor microenvironment, Dhodapka said. This finding has broad implications for the CAR T-cell therapy field, as it emphasizes the importance of the patients preexisting immune microenvironment as a determinant of durable responses.

Investigators think that understanding the baseline factors that affect durable responses could help physicians identify individuals who would benefit from BCMA-targeted CAR T-cell therapy.

Furthermore, the results could introduce opportunities to study combination therapies that target cell types or specific markers associated with relapse.

Reference

Specific components of the tumor immune microenvironment may affect the durability of responses to BCMA CAR T-cell therapy. News release. American Association for Cancer Research. August 29, 2022. Accessed August 30, 2022. https://www.aacr.org/about-the-aacr/newsroom/news-releases/specific-components-of-the-tumor-immune-microenvironment-may-affect-the-durability-of-responses-to-bcma-car-t-cell-therapy/

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Study: New Factors Are Associated With Increased PFS from BCMA-Targeted T-Cell Therapy - Pharmacy Times

A study led by researchers at the University of Arizona Health Sciences discovered new information about the inner workings of the immune system that could have a profound impact on T cell therapies for cancer and other diseases.

T cells are a type of white blood cell essential to the immune system and defending the body against infection. The CD4 molecule is found on the surface of many T cells and has historically been thought to only play a supporting role in the cells functions. The paper, Enhancing and inhibitory motifs regulate CD4 activity, published in eLife, shows CD4 plays a more active role in regulating T cell receptor signaling.

The study took a unique evolutionary approach to the immune system by examining the ways T cells have changed or remained the same over time. Michael Kuhns, PhD, associate professor in the UArizona College of Medicine Tucsons Department of Immunobiology, and Koenraad Van Doorslaer, PhD, assistant professor in the UArizona College of Agriculture and Life Sciences School of Animal and Comparative Biomedical Sciences, assembled a team that focused on the evolution and function of CD4.

This study is giving us a better appreciation for how CD4 works in concert with the T cell receptor to naturally direct T cells, said Dr. Kuhns who serves on theCenter for Advanced Molecular and Immunological Therapies advisory committee. CD4 is very much a co-equal player in antigen recognition and T cell activation.

The findings allow researchers to paint a more accurate evolutionary blueprint of the mechanisms within CD4 that could allow for even more powerful versions of T cell therapy. Chimeric antigen receptor (CAR) T cell therapy is already being used for some forms of cancer. Dr. Kuhnsandresearchers at the Harvard Medical School-affiliated Joslin Diabetes Center, are currently testing genetically engineered five-module CAR T cells as a possible treatment for Type 1 diabetes.

Drs. Kuhns and Van Doorslaer, both members of theBIO5 Institute, looked at CD4 from several different species, from fish to human, to explore more than 400 million years of the molecules evolution. They identified regions in CD4 that are unique to mammals.

We looked at what amino acids in these proteins changed, and what amino acids in these proteins stayed the same, Dr. Van Doorslaer said. The idea being, if they didn't change, they could be important for the function of the protein.

The research team discovered conserved sequences of amino acids, called motifs, then worked to find out how the motifs enhanced or inhibited CD4 activity. They designed genes with mutated motifs and introduced them into a T cell system, then looked at the proteins response where it went in the cell, what it interacted with, and how it impacted signaling events and outcomes. They found different combinations of motifs resulted in varying degrees of upregulation and downregulation.

If you think about T cells as being driven by molecular machines, what we do is take the machines apart to figure out how they were built, Dr. Kuhns said. CD4 seems to be really important to the function of T cells, because evolution doesn't want it to change. We went in and changed it, which is like looking at how the car works in the absence of the tires.

More work needs to be done to measure the differing contributions the motifs make to CD4 function. Eventually, the research could lead to the engineering of more finely tuned synthetic receptors for T cell therapies.

The research reported on in this release was supported in part by the National Institute of Allergy and Infectious Diseases (R01AI101053).

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Study Uncovers Possible Path for Improving T Cell Therapies - University of Arizona

-- 3.2 Month Survival Benefit Demonstrated in Patients who had Already Received Prior Endocrine-based Therapy and at Least Two Prior Chemotherapies --

-- Trodelvy Now Shows a Survival Benefit in both Pre-treated HR+/HER2- Metastatic Breast Cancer and Second-Line Metastatic Triple-Negative Breast Cancer --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced the positive overall survival (OS) results from the Phase 3 TROPiCS-02 study evaluating Trodelvy (sacituzumab govitecan-hziy) versus comparator chemotherapy (physicians choice of chemotherapy, TPC) in patients with HR+/HER2- metastatic breast cancer who received endocrine-based therapies and at least two chemotherapies. In the study, Trodelvy demonstrated a statistically significant and clinically meaningful improvement of 3.2 months in OS compared to TPC (median OS: 14.4 months vs. 11.2 months; hazard ratio [HR]=0.79; [95% confidence interval [CI]: 0.65-0.96]; p=0.02). OS was a key secondary endpoint of the trial.

These findings will be presented on Friday, September 9 at 4:20pm CEST during the European Society for Medical Oncology (ESMO) Congress 2022 as a late-breaking oral presentation (#LBA76) in the Brest Auditorium, Paris Expo Porte de Versailles.

Other key secondary endpoints including objective response rate (ORR) demonstrated statistically significant improvement in favoring Trodelvy versus TPC. Time to deterioration (TTD) of Global Health Status/Quality of Life (QoL) and Fatigue scale per EORTC-QLQ-C30 also favored Trodelvy versus TPC (QoL: 4.3 months vs. 3.0 months, p=0.006; Fatigue: 2.2 months vs. 1.4 months, p=0.002). No statistically significant difference in TTD on the Pain Scale was observed.

It is outstanding to see a clinically meaningful survival benefit of over three months for patients with pre-treated HR+/HER2- metastatic breast cancer, said Hope S. Rugo, MD, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center, U.S. Nearly all patients with HR+/HER2- metastatic breast cancer will develop resistance to endocrine-based therapies even in combination with targeted agents, so these data are welcome news for the breast cancer community. The results of TROPiCS-02 highlight the potential for sacituzumab govitecan in patients with pre-treated HR+/HER2- metastatic breast cancer.

The safety profile for Trodelvy was consistent with prior studies, with no new safety signals identified in this patient population.

With these data from TROPiCS-02, Trodelvy has now demonstrated a survival benefit in both pre-treated HR+/HER2- metastatic breast cancer and second-line metastatic TNBC two difficult-to-treat forms of breast cancer, said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. Our Gilead Oncology ambition is to transform care for people with cancer, and the meaningful improvement in survival benefit seen in the TROPiCS-02 study with Trodelvy is another step forward in pursuing this ambition for patients.

The TROPiCS-02 study met its primary endpoint of progression-free survival earlier this year; detailed results were presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Trodelvy has not been approved by any regulatory agency for the treatment of HR+/HER2- metastatic breast cancer. Its safety and efficacy have not been established for this indication. Gilead has submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) based on data from TROPiCS-02; these data will also be shared with health authorities outside the U.S.

Sacituzumab govitecan-hziy is currently included in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines)i. This includes a Category 1 recommendation for use in adult patients with second-line metastatic triple-negative breast cancer (defined as those who received at least two prior therapies, with at least one line for metastatic disease). It also has a Category 2A preferred recommendation for investigational use in HR+/HER2- advanced breast cancer after prior treatment including endocrine therapy, a CDK4/6 inhibitor and at least two lines of chemotherapy.

Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information.

About HR+/HER2- Breast Cancer

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases, or nearly 400,000 diagnoses worldwide each year. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 30%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor.

About the TROPiCS-02 Study

The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at https://clinicaltrials.gov/ct2/show/NCT03901339.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 35 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. Trodelvy is also approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with locally advanced or metastatic urothelial cancer (UC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

Trodelvy is also being developed for potential investigational use in other TNBC and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer, metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

U.S. Indications for Trodelvy

In the United States, Trodelvy is indicated for the treatment of:

U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 61% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever.

Diarrhea: Diarrhea occurred in 65% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of patients. One patient had intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic reactions was 0.3%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 66% of all patients treated with Trodelvy and Grade 3 nausea occurred in 4% of these patients. Vomiting occurred in 39% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 67% in patients homozygous for the UGT1A1*28, 46% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 25% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 11% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence 25%) were fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence 25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPHY study (IMMU-132-06), the most common adverse reactions (incidence 25%) were diarrhea, fatigue, neutropenia, nausea, any infection, alopecia, anemia, decreased appetite, constipation, vomiting, abdominal pain, and rash. The most frequent serious adverse reactions (SAR) (5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence 25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.

Please see full Prescribing Information , including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gileads ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials, including those involving Trodelvy; uncertainties relating to regulatory applications for Trodelvy and related filing and approval timelines, including with respect to the pending sBLA for Trodelvy, and pending or potential applications for the treatment of metastatic TNBC, mUC, HR+/HER2- breast cancer, NSCLC, SCLC, head and neck cancer, and endometrial cancer, in the currently anticipated timelines or at all; Gileads ability to receive regulatory approvals for such indications in a timely manner or at all, and the risk that any such approvals may be subject to significant limitations on use; the possibility that Gilead may make a strategic decision to discontinue development of Trodelvy for such indications and as a result, Trodelvy may never be commercialized for these indications; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gileads Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties, and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements.

U.S. Prescribing Information for Trodelvy including BOXED WARNING, is available at http://www.gilead.com .

Trodelvy, Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies.

For more information about Gilead, please visit the companys website at http://www.gilead.com , follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

i Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer Version 4.2022. National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed August 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220906006036/en/

Jacquie Ross, Investorsinvestor_relations@gilead.com

Nathan Kaiser, MediaNathan.kaiser@gilead.com

Source: Gilead Sciences, Inc.

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Trodelvy Significantly Improved Overall Survival in Pre-Treated HR+/HER2- Metastatic Breast Cancer Patients in TROPiCS-02 Study - Gilead Sciences

A team of Israeli researchers based at Tel Aviv University have recently published research showing that eliminating or inhibiting the ability of brain cells called astrocytes to provide energy to glioblastoma cells resulted in cancer cell death and tumor regression. The team developed a method to achieve these results after discovering two mechanisms in the brain that support tumor growth and survival. One protects cancer cells from the immune system, and the other supplies the energy required for rapid tumor growth. Both mechanisms are controlled by astrocytes and, in their absence, the tumor cells die and are eliminated.

Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment, the researchers noted in their paper published in the journal Brain. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors.

The study was led by doctoral candidate Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH).

For their study, the researchers used an animal model that allowed them to eliminate active astrocyte around the tumor. Applying their method to eradicate the astrocytes, the investigators found that all the cancer disappeared in the animals within days and all the animals survived. Animals that had the presence of astrocytes near their tumor all died within five weeks.

Here, we tackled the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells, Mayo said. Specifically, we studied astrocytesa major class of brain cells that support normal brain function. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases.

In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapseindicating that the astrocytes are essential to tumor progression and survival, Mayo continued. But why did the astrocytes behave this way, essentially changing from cells that support normal brain activity to ones that help foster tumor growth. To get to the bottom of this, the researchers compared the gene expression profiles of astrocytes from health brains with those from glioblastoma tumors.

The team found two significant differences. The first related to how the immune system responded to glioblastoma. The tumor mass includes up to 40% immune cells mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes persuade them to change sides and support the tumor instead of attacking it, Mayo said.

The second change noted was how the astrocytes helped modulate glioblastomas access to energy needed to thrive, via the production and transfer of cholesterol to tumor cells. The investigators hypothesized that since the tumor cells were reliant on the cholesterol produced by the astrocytes as their main source of energy, eliminating it would starve the tumor.

To test their theory, Mayo and team engineered astrocytes near the tumor to stop expressing the specific proteinABCA1that transports cholesterol, effective preventing it from supplying the tumor. This method also produced good results, with the glioblastoma tumor dying within days. The researchers achieved these results in both animal models and glioblastoma samples taken from human patients.

This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerabilitythe tumors dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity, Mayo concluded.

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Manipulating Astrocytes in Tumor Environment Effective Against Glioblastoma - Inside Precision Medicine

This month Jane Fonda, the Oscar-winning actress, and activist, announced she has been diagnosed with non-Hodgkins lymphoma (NHL), a type of cancer.

Fonda, 84, shared the news in a post on her Instagram account.

So, my dear friends, I have something personal I want to share, she wrote. Ive been diagnosed with non-Hodgkins lymphoma and have started chemo treatments.

However, her outlook was positive. This is a very treatable cancer, she continued. 80% of people survive, so I feel very lucky.

According to the American Cancer Society, NHL is a common cancer in the US accounting for 4% of all cases. The group estimates that in 2022 around 80,500 adults and children will be diagnosed with the disease.

This isnt Fondas first experience with cancer. She has previously spoken of having skin cancers removed, along with a non-cancerous tumor in her breast (before having a mastectomy several years later).

NHL is a cancer of one of your immune cells, lymphocytes. Its one of your blood cells, and their normal function is to fight infection, Dr. Dima El-Sharkawi, consultant hematologist at The Royal Marsden NHS Foundation Trust in London, told Healthline.

However, theres not just one type of NHL.

When we say NHL, thats a pretty wide umbrella, Dr. Guillermo de Angulo, pediatric hematologist/oncologist at KIDZ Medical Services in Florida, explained to Healthline.

It could be anything from a B cell lymphoma or a T cell lymphoma to a Burkitts lymphoma or what we call anaplastic large cell, he continued.

El-Sharkawi added that most NHL cases are B cell lymphomas and broadly speaking, they can be high-grade or low-grade.

High-grade lymphomas, she shared, involve more rapid cell turnover. As such, patients typically present as more unwell and with a greater number of symptoms.

On the other hand, low-grade lymphomas grow at a slower rate and are sometimes not discovered until a patient has a scan or test for another reason.

It has not been disclosed which subtype of NHL Fonda has. But, due to the high cure rate she pointed to, both El-Sharkawi and de Angulo said it may be a high-grade B cell lymphoma.

When you talk about lymphomas, we divide them into two groups: Hodgkins lymphoma (HL) and NHL, de Angulo said.

HL has certain characteristics, and we look for certain proteins or markers that identify and confirm whether it is Hodgkins. If its [doesnt have these], we classify it as NHL.

According to de Angulo, the symptoms of NHL are similar to HL. One of the signs we often see, he said, is an enlarged lymph node or a palpable mass.

These typically occur in the neck, armpits, or groin area but, in rarer instances, can present in other areas of the body.

Patients can have lymphoma affecting their stomach or liver, and you can even get lymphoma affecting the brain, El-Sharkawi stated.

The location of the mass or enlarged node can lead to secondary symptoms. For example, if [it] is in an area where its compressing a structure or pressing a nerve, it can cause irritation or pain, shared de Angulo.

Aside from an enlarged node or mass, there are several other key signs, including:

The only way to definitively diagnose NHL is to biopsy the affected area, stated El-Sharkawi, because there are other reasons for swollen glands and enlarged lymph nodes.

In most cases, there are no known causes of NHL, Dallas Pounds, director of services at UK-based charity Lymphoma Action, told Healthline.

However, its thought there may be a few potential risk factors.

In terms of genetics, theres no particular gene linked to the development of NHL unlike some other types of cancer, like breast cancer.

That said, there does seem to be some familial predisposition, noted El-Sharkawi. If youve got a first-degree relative with NHL, then you are slightly more likely (over the general population) to get it [but] its still very rare.

Fondas age may be a factor in her diagnosis. Generally speaking, NHL is more common in the over-60s and 70s, El-Sharkawi said. However, she added, it can be in any age group children may develop NHL.

De Angulo explained that individuals with existing health conditions such as certain autoimmune diseases may also be at higher risk of NHL. People that have undergone certain forms of treatment, such as for ulcerative colitis or lupus, can [have] increased risk of lymphoma.

Furthermore, patients who have undergone solid organ transplants (such as liver or kidney) are also sometimes at greater risk, he said. This is because of the immunosuppressive medications they have to take after the operation.

When youve had a solid organ transplant, you want to suppress the immune system so you dont reject the organ thats been transplanted, he explained. But, that same immune system is the one that makes sure you dont get lymphoma.

Every person diagnosed with lymphoma will have an individual treatment plan depending on them as an individual and their presenting symptoms, said Pounds.

While low-grade lymphomas grow more slowly, they are only treatable but not curable with current therapies.

High-grade lymphomas, however, are potentially curable with chemotherapy, explained El-Sharkawi. Because [they] are more rapidly dividing, theyre more susceptible to the chemo, which essentially targets the ability of those cells to divide and proliferate.

Chemotherapy is generally used because, unlike targeted therapies, such as radiotherapy or surgery, the treatment can reach numerous areas. This is critical as blood is constantly moving around the body.

Additionally targeted antibody therapy is given in combination with chemotherapy, which can increase the chances of remission.

Fonda shared that she has started six months of chemotherapy treatments. These are primarily conducted on an outpatient basis, de Angulo said, and administered across six cycles.

Other treatments for lymphomas are available, although these tend to be in relapsed/refractory [high-grade patients] so when the disease has either come back after treatment or they didnt respond, noted El-Sharkawi.

These include smart drugs, stated de Angulo, which attack the cells that express a certain antigen.

Another option is called CAR-T therapy. [This] is an exciting new way of treating lymphoma, El-Sharkawi enthused. Essentially, the patients T cell lymphocytes are manipulated in a laboratory setting so that they know to target the B lymphocytes, before being put back into the body.

Its like a living medicine made from their own blood cells, she added.

NHL is a type of blood cancer that impacts the immune cells and is one of the most common cancers in the US. It can affect people of all ages but is more often seen in those over 60.

There are numerous NHL subtypes, but symptoms generally include an enlarged lymph node or mass, night sweats, tiredness, and weight loss.

Chemotherapy is the most popular treatment type, although new targeted therapies continue to emerge and be of benefit.

The outlook for an individual with non-Hodgkins lymphoma will depend on several factors, said Pounds. But many people will respond well to treatment and enter a time of remission or stability after it.

Link:
Jane Fonda Diagnosed with Non-Hodgkin's Lymphoma: What to Know - Healthline