Category: Cancer and neoplasms

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Shahneen Sandhu, PhD, MBBS, FRACP Early findings from the phase 1 LuPARP study (NCT03874884) demonstrated that patients with metastatic castration-resistant prostate cancer (mCRPC) experienced enhanced antitumor activity following treatment with the PARP inhibitor olaparib (Lynparza) in addition to the radioligand lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617).1 Among 32 patients treated across dose levels, the prostate-specific antigen (PSA) response rate of at least 50% was observed in 66% of patients, with 14 of the 32 patients (44%) achieving a PSA response of at least 90%. The overall response rate was 78%. Further, safety findings showed that no dose-limiting toxicities were reported across dose levels.1 “I think this is intriguing data, although early, but may be suggestive of a deepening of responses from the combination therapy,” Shahneen Sandhu, PhD, MBBS, FRACP, said in a presentation of the data during the 2023 ASCO Annual Meeting. “And the reason that’s important is we do know, based on other data sets, that a PSA response of 90% does in fact, translate into improved progression-free survival [PFS].” “Lutetium-PSMA-617 is a radioligand therapy that is directed to prostate-specific membrane antigen [PSMA] and has previously been shown to improve both PFS and overall survival [OS],” Sandhu, who is an associate professor in the Department of Medical Oncology and a consultant medical oncologist and researcher in the melanoma and uro-oncology units at the Peter MacCallum Cancer Center in Melbourne, Australia said. “Olaparib is a potent PARP inhibitor that has also been shown to improve PFS and OS in men with mCRPC with an underlying DNA repair defect or homologous recombination repair defect. Both Lutetium-PSMA-617 and olaparib are very well-tolerated and are widely used. Lutetium-PSMA-617 delivers a payload of beta radiation to PSMA-expressing tumors. Lutetium-PSMA-617 predominantly causes single strand DNA breaks. And these DNA breaks are repaired by PARP-dependent base excision repair. Therefore, blocking PARP could result in conversion of DNA single strand breaks to more lethal double strand breaks [via] fork collapse.” Forty-eight patients with prostate-specific membrane antigen (PSMA) avidity were enrolled to LuPARP. This was defined as those with a minimum uptake of SUVmax of 15 at a site of disease, and SUVmax greater than 10 at other sites of disease measuring at least 10 mm identified using 68Ga/18F-PSMA PET/CT.2 Patients received olaparib 50 to 300 mg orally in a 3 + 3 dose escalation lutetium Lu 177 vipivotide tetraxetan was administered every 6 weeks for 6 cycles at 7.4 GBq. Biomarker collection and imaging occurred as follows: PSMA PET/CT at baseline and every 12 weeks for 48 weeks, then every 24 weeks; FDG PET at baseline; bone scan and CT-CAP at baseline then every 12 weeks; blood and biomarker analysis for PBMC, circulating tumor cells, circulating tumor DNA, serum levels were done very 12 weeks and at disease progression; tumor biopsies were obtained for archival storage at base line, between weeks 2 to 4, and at disease progression.1 Nine cohorts were included in the dose-escalation design. Patients in cohort 1 (n = 3) received olaparib at 50 mg, at 100 mg in cohort 2 (n = 3), at 150 mg in cohort 3 (n = 3), at 200 mg in cohort 4 (n = 3), at 250 mg in cohort 5 (n = 4), and at 300 mg in cohort 6 (n = 3). Each of these cohorts had olaparib administered on days 2 through 15. Those in cohort 7 (n = 4) received olaparib at 200 mg and those in cohort 8 received the agent at 300 mg on days –4 through 14. Finally, those in cohort 9 (n = 6) received olaparib at 300 mg on days –4 through 18. The median number of treatment cycles across populations was 5 (range, 2-6). Specifically for cohorts 1-9 the median cycles of treatment were 4 (range, 4-5); 6 (range, 5-6); 6 (range, 2-6); 3 (range, 2-4); 6 (range, 4-6); 6 (range, 5-6); 5.5 (range, 3-6); 4 (range, 3-6); and 3 (range, 2-5).1 Overall, most adverse events (AEs) were grade 1 or 2. Grade 1 events included anemia (n = 5), neutropenia (n = 1), thrombocytopenia (n = 5), nausea (n = 13), dry mouth (n = 22), constipation (n = 7), vomiting (n = 3), gastroesophageal reflux (n = 2), diarrhea (n = 3), weight loss (n = 1), anorexia (n = 6), dry eye (n = 2), and fatigue (n = 15). Grade 2 events were anemia (n = 3), thrombocytopenia (n = 2), nausea (n = 6), dry mouth (n = 3), constipation (n = 2), vomiting (n = 1), gastroesophageal reflux (n = 1), and weight loss (n = 1).1 Grade 3 events occurred in cohorts 5 and 6 at the 250-mg and 300-mg dose levels for olaparib, respectively. In cohort 5, these events 1 each of anemia, thrombocytopenia, and neutropenia, which was deemed a serious treatment-related AE and classified as febrile neutropenia. In cohort 6, the grade 3 events were 1 instance each of anemia and neutropenia. No grade 4 events were reported.1 Dose reductions because of treatment-related AEs occurred in 9% of patients overall, including 1 patient each from cohorts 3, 5, and 6. Two dose delays were reported 1 each in cohorts 3 and 6. Sixteen patients will be enrolled to the dose-expansion phase to receive the recommended dose of olaparib: 300 mg orally on days –4 to 18 of each 6-week cycle. The primary end points are dose-limiting toxicities (DLTs) and recommended phase 2 dose. The secondary end points are safety and antitumor activity including radiographic PFS, PSA response rate, PSA PFS, overall response rate, and OS. Following completion of therapy, patients are required to attend an end of treatment visit and will be followed for PFS and OS outcomes.1 Of note at the time of data cutoff, patients enrolled in cohorts 8 and 9 were in early treatment cycles. The median age was 71 years (range 52-84) with 56% of patients having an ECOG performance status of 0 and the remaining 44% having a status of

The core foundation of precision medicine, and in turn, precision oncology, is a personalized approach to treatment that focuses on targeting specific molecular features that impact how cancer cells proliferate and spread. Targeted therapies, often exploiting specific proteins present on the surface of cancer cells, provide additional avenues for patients whose tumors express these targets, leading to more favorable outcomes than standard therapy alone. In prostate cancer, “PSMA [prostate specific membrane antigen] is the most comprehensively validated cell surface target,” said Dr. Erolcan Sayar, a postdoctoral research fellow in the Haffner Lab, part of Fred Hutch’s Human Biology Division. In recent years, great strides have been made in targeting PSMA for treatment, with radioligand therapy 177Lu-PSMA-617 receiving FDA approval for treating patients with advanced prostate cancer. “However, the expression levels of PSMA can vary among different tumors and even within the same tumor. The impact of heterogeneous PSMA expression on treatment options is primarily related to the use of PSMA-targeted therapies. These therapies, such as PSMA-targeted radionuclide therapy (e.g., 177Lu-PSMA-617), rely on the presence of PSMA on the surface of cancer cells for their effectiveness. Prior clinical trials have suggested that patients with low or heterogenous PSMA expression show reduced therapeutic benefit from PSMA-directed therapies,” explained Dr. Sayar. Based on this, Dr. Sayar, under the mentorship of Dr. Michael Haffner, led a study recently published in JCI insight, to better understand the heterogeneous expression patterns and molecular underpinnings of PSMA, with the goal of improving treatment options for patients with metastatic castration resistant prostate cancer (mCRPC), a lethal disease state. For their study, the authors extensively profiled samples derived from patients with mCRPC and determined variable broad expression patterns across different subtypes of the disease. For example, tumors that rely on the androgen receptor for proliferation exhibited diverse PSMA expression patterns, while neuroendocrine tumors had generally lower expression of PSMA at both the mRNA and protein level. Next, to assess both inter- and intra-tumoral heterogeneity, the authors profiled samples derived from multiple distinct metastatic sites within the same patient with mCRPC. “A major advantage of our tissue donation based study is the ability to study multiple metastatic sites in a given patient. This setting allows for the detailed evaluation of inter- and intra-tumoral heterogeneity. We are grateful to the patients and their families for their contributions to the UW Medical Center Prostate Cancer Tissue Donation Program,” expressed Dr. Sayar. They observed substantial intertumoral (between different metastatic sites) heterogenous PSMA expression, in addition to heterogeneous expression of PSMA present intratumorally (between different spatial sites within one metastatic lesion).

Giving patients with operable pancreatic cancers a three-pronged combination immunotherapy treatment consisting of the pancreatic cancer vaccine GVAX, the immune checkpoint therapy nivolumab and urelemab, an anti-CD137 agonist antibody treatment, is safe, it increases the amount of cancer-killing immune system T cells in the tumors and it appears effective when given two weeks prior to cancer-removal surgery, according to new research directed by Johns Hopkins investigators. A description of the work was published online June 20 in the journal Nature Communications. This study, led by researchers at the Johns Hopkins Kimmel Cancer Center, the Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins University School of Medicine, is the latest from an ongoing platform trial formed in 2015 to study immunotherapy treatments before surgery (neoadjuvant) and after surgery (adjuvant) for patients with pancreatic cancer. This format enables researchers to use data generated by the trial to advance development of immunotherapies for pancreatic cancer within the same study. In this most recent part of the trial, 10 participants received the combination treatment. The median disease-free survival — the amount of time after treatment during which no cancer is found — was 33.51 months, and the median overall survival — time to death — was 35.5 months. These were higher than found in previous arms of the trial that tested the pancreatic cancer vaccine alone and in combination with nivolumab, but because of the small number of patients, the results did not have statistical significance. The tumor specimens studied in the recent arm also had much higher amounts of cancer-killing immune cells than specimens from patients given only the vaccine or the vaccine plus nivolumab. The results suggest that this therapy combination warrants further study in a larger clinical trial, says senior study author Lei Zheng, M.D., Ph.D., co-director of the Pancreatic Cancer Precision Medicine Center of Excellence and professor of oncology at the Johns Hopkins University School of Medicine. The platform trial has two purposes regarding pancreatic cancer treatments given during the two-week “window of opportunity” prior to surgery, Zheng says. First, it allows the immunotherapies to teach the patient’s immune cells how to respond to tumors, so they can continue surveillance later if the cancer recurs. Second, it enables investigators to see, by evaluating the tumors removed during surgery, how well the tumors respond to the treatment. A fourth arm of the trial, studying anti-interleukin-8 neutrophil-blocking antibodies in pancreatic tumors, is ongoing. Zheng is available for comment. To schedule an interview, contact Valerie Mehl at [email protected] or Amy Mone at [email protected]. Journal Nature Communications Article Publication Date 20-Jun-2023 Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Before they were able to develop the promising HER2 DNA vaccine highlighted in this study, figuring out how to make an effective vaccine against cancer took some trial and error. Dhillon explained that “the real breakthrough came about eight years ago when we developed an understanding of how the same protein, or antigen, could have different responses from the immune system.” For instance, one part of the protein may elicit a strong tissue destructive response that kills off cancer cells, while another part may promote disadvantageous immune suppression. Excitingly, Dhillon exclaimed “we’ve figured out this system and now we’ve got a hammer to combat cancer.” Knowing that each cancer comes with unique treatment challenges, the CVI researchers designed vaccines to work at three stages of cancer therapy: cancer prevention, treatment, and recurrence. While these vaccines aren’t designed to work quite like our yearly flu shot, they’re aimed to either help prevent cancer in high-risk patients (prevention or interception), work in conjunction with current chemotherapies to boost their effectiveness (treatment) or help keep cancers from coming back after they’re initially treated (recurrence). Cancer vaccines all generally work by “training the immune system to recognize cancer cells expressing specific proteins as dangerous, setting off alarms and signaling to attack those cells,” Dhillon explained. These trained T cells survey the body including the brain, which is a common site of breast cancer metastasis and difficult to target since many drugs cannot cross the blood-brain barrier. Thus, this approach can overcome one of the current challenges of drug-based therapeutic regimens. To focus on treating this aggressive breast cancer, with hammer in hand, Disis and the CVI research team developed a DNA vaccine encoding the HER2 protein intracellular domain (thus training the immune system to attack HER2-expressing cancer cells) to treat 66 patients with stage III or IV HER2-positive breast cancer. Prior to vaccination, all patients had been effectively cured of cancer through treatment with chemotherapy drugs like Trastuzumab. Although patients were technically cancer-free at this pre-vaccine stage, HER2-positive breast cancers are aggressive with a high probability of recurrence and metastasis. But this is where the vaccine steps in! The patients were given one of three monthly doses of this DNA vaccine over a 3-month period. Vaccines were found to be very safe with extremely mild adverse effects, similar to the aches and chills one might experience from COVID-19 or flu vaccines- a walk in the park compared to current, more toxic, cancer treatments. Disis and colleagues then assessed the patients’ immune responses to the vaccines by analyzing blood samples taken at various post-vaccination timepoints. Teaming up with Dr. Katherine Guthrie, a Professor in the Cancer Prevention Program at Fred Hutch, to analyze the patient data, the researchers observed a strong immune response to all doses of vaccines administered. However, the middle dose seemed to be the most effective with a sustained immune response over time. This immune response was accompanied by an increase in central memory T cells, which are important for long-term immunity. Furthermore, at this dose, the mean survival after a 10-year period for these late stage breast cancer patients was ~85% among stage III and IV patients, remarkably with all of the stage III women still alive today. Comparatively, the survival rate for stage III/IV breast cancer patients receiving currently available chemotherapies is only 50% at just 4.5 years post-treatment. The remarkable increased survival rates for this phase I clinical trial emphasize the effectiveness of vaccines for this aggressive breast cancer and bring hope that effective, affordable and accessible vaccine-based cancer treatments might be a future reality for other cancers. Partnering with Aston Sci., the vaccine developed at CVI is headed into phase II randomized clinical trials which will be expanded to include patients with other types of difficult-to-treat breast cancers who might benefit from a HER2-targeted therapeutic approach. It is important to note that final approval by the FDA for use outside of clinical trials will require even larger phase III randomized trials that rigorously test efficacy. As an off the shelf cancer therapy, vaccines are emerging as a promising new treatment that could be broadly available, affordable, safe, and effective, with adverse effects being no worse than a COVID-19 shot. In addition to the research teams at CVI, these exciting breakthroughs would not have been possible without the work of several key players, including the UW/Fred Hutch/Seattle Children’s Cancer Consortium Women’s Cancer Program, which helped recruit patients for clinical trials, and Fred Hutch’s GMP facility which manufactured the vaccines for this work. While Dhillon is excited about the scientific results of this study, she emphasized how integral the patients are in this. Dhillon stressed how grateful CVI is for the patients, “as nothing we do would be possible without them. We keep the patients at the center of everything we do.” Living this value, the CVI team gives back to patients through hosting patient reunion and educational events to teach people about cancer vaccines and clinical trials, with a focus on holding these events for diverse communities that are not well represented in clinical trials. Underscoring the strong relationship CVI builds with their patients, Dhillon shared that more than 10 years after the HER2 vaccine clinical trial, one patient recently called her to say: “I’m still here!” This simple phone call may not have been possible without this breast cancer vaccine. For those interested in learning more clinical trials, please check out the resources below! -To learn more about current UW CVI clinical trials and the contact information for these studies for those interested in enrolling, see here. -To learn more about how to participate in clinical trials and the risks and benefits involved, see here.

Introduction Mucinous breast carcinoma (MBC) is a comparatively rare specific carcinoma of breast featuring much extracellular mucus and favorable prognosis.1,2 Moreover, MBC takes a proportion of 1–4% in all primary breast cancers approximately. Several factors can influence the prognosis of MBC, including age, stage of the disease, and specific histological features. Although MBC is generally associated with a favorable prognosis, older age at diagnosis can be a negative prognostic factor. Elderly patients may have comorbidities or age-related physiological changes that can impact treatment decisions and overall outcomes. In the existing literature, MBC morbidity is rather high among the elderly, that is about 6–7%.3 Pathologically, there are two subtypes of MBC according to the content of intratumoral mucus. One is pure mucinous breast carcinoma (PMBC); and the other is mixed mucinous breast carcinoma (MMBC). While PMBC is merely constituted by tumor cells producing mucus and the proportion taken by mucus components in the tumor is at least 90%, mucus in MMBC takes a proportion of 50–90% and is also mixed with infiltrating ductal epithelium.4,5 As demonstrated in many studies, PMBC is an indolent tumor characterized by good prognosis and low axillary lymph node metastasis rate;6,7 and by contrast, MMBC exhibits distinct biological behavior from PMBC.8 In recent years, it is clarified in some research that some PMBC is as invasive as MMBC.6,9 For example, Ranade et al point out10 that micropapillary structures can be observed in 60% PMBCs with axillary node positive and 14% PMBCs with axillary node negative. This manifests that the micropapillary structure plays a critical role in progression of axillary node metabasis. As early as 2002, a novel subtype of PMBC was reported by Ng11 for the first time; and it was named mucinous carcinoma with micropapillary pattern, or MUMPC for short. However, MUMPC alignment is believed in some literature to be similar to that of invasive micropapillary carcinoma; and MUMPC is more inclined to be associated with biological behavior of infiltrating tumors, such as lymphatic metastasis and lymphovascular invasion. According to Barbashina et al.12 MUMPC is an invasive subtype in clinics of mucinous breast cancers and should be differentiated from conventional pure mucinous breast carcinoma without micropapillary architecture (cPMBC). Micropapillary patterns consist of small, finger-like projections of tumor cells floating within mucus pools. Micropapillary structures have been associated with increased invasiveness, lymphatic metastasis, and poorer clinical outcomes in various types of breast carcinoma. Understanding the significance of micropapillary patterns is essential for accurate diagnosis and management of these tumors. Therefore, further investigation into the role and implications of micropapillary patterns in mucinous breast carcinoma, particularly in MUMPC, is warranted for better characterization and treatment strategies. To our knowledge, MUMPC is seldom explored at present, especially relevant literature describing its ultrasound findings. Therefore, the Breast Imaging Reporting and Data System (BI-RADS) was utilized in this paper to carry out ultrasound examinations on MUMPC, analyze ultrasound features of MUMPC, and then compare MUMPC with cPMBC or MMBC. Methods Participants We retrospectively analyzed 872 patients with breast cancer who received relevant therapies at Suzhou Municipal Hospital from January 2015 to June 2019. Based on the classification of breast neoplasms by the World Health Organization (WHO), content of mucus in PMBC exceeds 90%, while that of MMBC is below 90%.13 As for the lower limit of mucus content in MMBC, it remains unsolved. The corresponding inclusion criteria are as follows: (1) the performance status of Eastern Cooperative Oncology Group (ECOG) is 0 or 1; (2) the patients are histopathologically diagnosed with MBC; (3) the patients should experience breast ultrasound and surgical excision; and (4) clinical pathological and ultrasonic data of the patients should be complete. Regarding the exclusion criteria, they are: (1) combined with distant metastasis; (2) being combined with other malignant tumors or a history of tumors; (3) bilateral breast cancers; and (4) male. In strict accordance with the above inclusion and exclusion criteria, 49 patients were incorporated at last, taking a proportion of 5.62% in the total number of patients with breast cancer, showing 49 lesions in total. All of them are females aged 28~84 (mean: 57; and median: 56), including 9 cases with MUMPC and 21 cases with MMBC. This study has been approved by the Ethics Committee of Suzhou Municipal Hospital; and the informed consent has been gained from all patients. Ultrasound Examinations Forty-nine patients were all subjected to ultrasonography of breast cancer by using a linear array probe (5–15 MHz). Ultrasound images were judged by a physician-in-charge uninformed of the corresponding pathological outcomes. More particularly, results of ultrasound examinations were also retrospectively analyzed by a sonographer with at least 6 years of experience based on standards specified in BI-RADS categories of image features. Sizes, shapes (regular/irregular), edges (smooth and complete or not), halo signs (yes or no), posterior echo (no alterations, enhancement or attenuation), internal echo (solid and cystic mixed echo, or solid hypoecho/isoecho), malignant halo (yes or no) and lymph node metastasis were all recorded. Besides, vascularity (being present or not) of breast lesions was retrospectively analyzed. By means of Adler’s semi-quantitative grading, blood flow conditions of lesions were classified into 4 grades: (1) Grade 0: No blood flow signals; (2) Grade 1: A few blood flow signals (characterized by 1 or 2 dotted/short rod-like color blood flow signals); (3) Grade 2: Medium blood flows (characterized by 3 or 4 dotted color blood flow signals, or by longer blood flows, probably half of the corresponding lump in length); and (4) Grade 3: Abundant blood flows (characterized by over 4 dotted color blood flow signals, or by two long blood flows). Tissue Pathology Breast lesions of all patients were surgically removed. For surgical pathological reports verified by well-experienced pathologists of Suzhou Municipal Hospital, they were all reviewed together with pathological results of ipsilateral lymph node metastasis (LNM). Statistical Analysis All outcomes are analyzed by SPSS 20.0 applicable to Windows (Microsoft). Both x2 and Fisher’s precise tests were performed to analyze shapes, edges, halo signs, posterior echo, internal echo, malignant halo, lymph node metastasis and grades

Frederick Locke, MD, a medical oncologist and translational researcher in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center, explains the allogeneic CD19-directed chimeric antigen receptor (CAR) T-cell therapies, ALLO-501 and ALLO-501A, and how the work. An investigation of ALLO-501 for the treatment of patients with large B-cell lymphoma is occurring in the phase 1 ALPHA study (NCT03939026), which aims to include 74 patients. Patients in the study will be treated with ALLO-501 in addition to ALLO-647 and lymphodepletion chemotherapy consisting of fludarabine and cyclophosphamide. The key end point being assessed in the study include dose-limiting toxicity of ALLO-501 and ALLO-647. ALLO-501A is an identical drug to ALLO-501, says Locke. The one difference between the agents is that ALLO-501A has no rituximab (Rituxan) kill switch. Both agents have a gene editing component, which allows for each agent to be used in combination with chemotherapy and a CD52-directed CAR T product, according to Locke. Transcript: 0:08 | ALLO-501 and ALLO-501A are off-the-shelf allogeneic CD19-directed CAR T-cell therapies. The only difference between ALLO-501 and ALLO-501A is that ALLO-501A has removed a rituximab kill switch, which was present in ALLO-501. Otherwise, they’re identical. These CAR T cells have gene editing. So, not only do they express the CD19 CAR, but their gene-edited. The track locus is removed so that the T cell receptor is not expressed and therefore, the cells are unlikely to cause graft-versus-host disease. 0:56 | The CAR T cells are gene-edited so that CD52, which is a cell surface protein that’s on immune cells, is removed from the CAR T cells and that actually allows us to also give an antibody against CD52 as part of the conditioning chemotherapy regimen, which ALLO-647. It’s a monoclonal antibody against CD52, which has been removed from those CAR T cells.