Category Archives: Stem Cell Therapy

Michael Hurwitz, MD, PhD, associate professor, internal medicine (medical oncology), Yale School of Medicine, discusses the ongoing investigation into the use of CAR T-cell therapies in patients with solid tumors, such as kidney cancers.

Hurwitz begins by stating that considerations surrounding the use of CAR T-cell therapy in solid tumors, such as renal cell carcinoma (RCC), have been uncertain. The phase 1 COBALT-RCC trial (NCT04438083), which investigated CTX130 allogeneic CRISPR/Cas9engineered CAR T-cell therapy in patients with advanced clear cell RCC, is currently inactive. However, a new agent with similar attributes to the CAR T-cell product investigated in COBALT-RCC is under development and may improve upon the outcomes seen in COBALT-RCC, Hurwitz begins.

Another trial, the phase 1 TRAVERSE trial (NCT04696731), is ongoing at some sites, he explains. This trial involves off-the-shelf CAR T-cell therapy, Hurwitz explains. These modified CAR T cells are engineered to evade the recipient's immune response and eliminate the need for personalized CAR T-cell production, offering a faster turnaround that is crucial for individuals with advanced solid tumors, Hurwitz explains.Traditionally, introducing foreign T cells into the body triggers immune responses, which are addressed by removing human leukocyte antigens, so the body does not recognize the T cells as foreign. In these modified CAR T cells, the endogenous T-cell receptors are also removed, ensuring these cells do not perceive the body as foreign, he expands.

Along with the FDA approvals of CAR T cells for patients with hematologic malignancies, their application in solid tumors is evolving, Hurwitz emphasizes. Ongoing preclinical research aims to engineer safe, specific, and effective CAR T cells, he states.

These innovations with CAR T-cell therapy promise highly targeted, safe cancer treatments for patients with solid tumors, Hurwitz continues. Looking forward, the possibility of synergies between CAR T-cell therapy and other treatments looms, he notes. Although the timing of integrating CAR T-cell therapies into the solid tumor treatment armamentarium is uncertain, combining these products with other agents offers a glimpse into a future where cancer treatment is more effective and personalized.In essence, technological advances in cancer therapy are just beginning to unfold, Hurwitz adds. The future promises innovations and a convergence of technologies to reshape cancer treatment, ushering in an era of hope and healing, he concludes.

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SEATTLE, Dec. 01, 2023 (GLOBE NEWSWIRE) -- Sana Biotechnology Inc. (NASDAQ: SANA), a company focused on changing the possible for patients through engineered cells, today announced the publication in Bloodof an abstract providing initial clinical data from the first patient treated at the lowest dose in the ongoing ARDENT Phase 1 clinical trial with SC291, a hypoimmune (HIP)-modified allogeneic CD19-directed CAR T cell therapy. SC291 appeared safe and well tolerated, evaded immune detection, and induced a partial response in a patient with chronic lymphocytic leukemia (CLL). ARDENT is a Phase 1 study evaluating safety and tolerability of SC291 in patients with CLL and non-Hodgkin lymphoma. Treatment in this dose escalation study is ongoing, and the company expects to present more data from this study at a later date in an appropriate venue.

These are the first clinical data demonstrating that our HIP technology can engineer allogeneic cells to evade adaptive and innate immune detection and rejection in the context of an intact immune system, overcoming the key challenge in unlocking the potential of allogeneic cells, said Gary Meininger, MD, Sanas Chief Medical Officer. These data suggest the potential of SC291 to persist and attack cancer cells in a manner consistent with autologous cells, which combined with scaled manufacturing, encourage us about both the opportunity for SC291 and our other HIP-modified cells to provide clinical benefit for patients. The data were published as part of an abstract submitted over the summer, and we look forward to sharing more data from this ongoing clinical trial that we expect will more clearly outline SC291s profile.

The full abstract is available for online viewingat https://doi.org/10.1182/blood-2023-179441.

About SC291 in B-cell Lymphomas or Leukemias SC291 is a hypoimmune, CD19-directed allogeneic CAR T cell therapy derived from healthy donor CD4+ and CD8+ T cells that are genetically engineered. SC291 is developed with Sanas hypoimmune platform, which is designed to overcome the immunologic rejection of allogeneic cells, which if true for SC291 may result in longer CAR T cell persistence and a higher rate of durable complete responses for patients with B-cell lymphomas or leukemias. The hypoimmune technology includes disruption of major histocompatibility (MHC) class I and MHC class II expression to allow cells to evade the adaptive immune system, which includes antibody and T cell responses, as well as overexpression of CD47 to evade the innate immune cell system, in particular macrophages and natural killer (NK) cells. The company has presented data across multiple preclinical models highlighting the potential of this platform to cloak cells from immune recognition and the potential of SC291 as a therapeutic for patients with B-cell malignancies. SC291 is being evaluated in a Phase 1 study called ARDENT for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).

About Hypoimmune Platform Sanas hypoimmune platform is designed to create cells ex vivo that can evade the patients immune system to enable the transplant of allogeneic cells without the need for immunosuppression. We are applying the hypoimmune technology to both donor-derived allogeneic T cells, with the goal of making potent and persistent CAR T cells at scale, and pluripotent stem cells, which can then be differentiated into multiple cell types at scale. Preclinical data published in peer-reviewed journals demonstrate across a variety of cell types that these transplanted allogeneic cells are able to evade both the innate and adaptive arms of the immune system while retaining their activity. Our most advanced programs utilizing this platform include an allogeneic CART program targeting CD19+ cancers, an allogeneic CAR T program for B-cell mediated autoimmune diseases, an allogeneic CAR T program targeting CD22+ cancers, and stem-cell derived pancreatic islet cells for patients with type 1 diabetes.

About Sana Biotechnology Sana Biotechnology, Inc. is focused on creating and delivering engineered cells as medicines for patients. We share a vision of repairing and controlling genes, replacing missing or damaged cells, and making our therapies broadly available to patients. We are a passionate group of people working together to create an enduring company that changes how the world treats disease. Sana has operations in Seattle, Cambridge, South San Francisco, and Rochester. For more information about Sana Biotechnology, please visit https://sana.com/.

Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements about Sana Biotechnology, Inc. (the Company, we, us, or our) within the meaning of the federal securities laws, including those related to the Companys vision, progress, and business plans; expectations for its development programs, product candidates and technology platforms, including its pre-clinical, clinical and regulatory development plans and timing expectations; the significance of initial data from the first patient treated in the ARDENT Phase 1 clinical trial; the Companys expectations regarding the timing and substance of future data from the ARDENT trial; the ability to use the HIP platform to create cells ex vivo that can evade a patients immune system and enable the transplant of allogeneic cells without the need for immunosuppression and the potential benefits associated therewith; and the ability to apply the HIP technology to allogeneic T cells to make potent and persistent CAR T cells at scale and to pluripotent stem cells, which can then be differentiated into multiple cell types at scale. All statements other than statements of historical facts contained in this press release, including, among others, statements regarding the Companys strategy, expectations, cash runway and future financial condition, future operations, and prospects, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as aim, anticipate, assume, believe, contemplate, continue, could, design, due, estimate, expect, goal, intend, may, objective, plan, positioned, potential, predict, seek, should, target, will, would and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. The Company has based these forward-looking statements largely on its current expectations, estimates, forecasts and projections about future events and financial trends that it believes may affect its financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. These statements are subject to risks and uncertainties that could cause the actual results to vary materially, including, among others, the risks inherent in drug development such as those associated with the initiation, cost, timing, progress and results of the Companys current and future research and development programs, preclinical and clinical trials. For a detailed discussion of the risk factors that could affect the Companys actual results, please refer to the risk factors identified in the Companys SEC reports, including but not limited to its Quarterly Report on Form 10-Q dated November 8, 2023. Except as required by law, the Company undertakes no obligation to update publicly any forward-looking statements for any reason.

Investor Relations & Media: Nicole Keith investor.relations@sana.com media@sana.com

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Sana Biotechnology Publishes Early Clinical Data Showing that ... - BioSpace

Several factors contribute to improving the success and safety of allogeneic stem cell transplant. At Roswell Park, we deploy three key strategies to help our patients achieve better outcomes and quality of life.

Effective GVHD prophylaxis

We use PTCy-based GVHD prophylaxis for all donor sources in the allogeneic setting. PTCy was developed as a GVHD prevention strategy for haploidentical transplantation but was later shown to be incredibly effective for related and unrelated donor transplants, regardless of match grade. By using PTCy, life-threatening acute GVHD is less than 10%, when we used to experience rates of 25% or even higher only 2 or 3 years ago.

This strategy has also reduced the risk for chronic GVHD requiring systemic immune suppression from 40-60%, down to 5-10%. This means number of patients requiring systemic immune suppression is also reduced, allowing us to avoid some other significant side effects such as infections, diabetes, and bone problems due to prolonged use of glucocorticoids. The fact that we can avoid all that and just make quality of life better for our patients and have better odds of curing them is fantastic.

Prioritizing donor age < 40

There is clear and consistent data showing the use of donors under 40 years of age improve outcomes for transplant recipients. Traditionally, determining an appropriate stem cell donor meant matching eight of eight human leukocyte antigens (HLA). While match-grade is still important, the use of PTCy allows us to tolerate HLA-mismatches of 6 or 7/8 and focus on identifying younger donors to improve transplant success.

So, our first choice is a fully matched, related donor, younger than age 40. If we dont have that we look at a matched, unrelated donor, also younger than age 40. Data from several multicenter sources now show the use of PTCy with mismatched donors yield phenomenal results. Therefore, our primary alternative donor source is a 6 or 7/8 HLA matched unrelated donor, followed by a haploidentical donor. This allows us to find donors for many more patients and younger donors than we used to improving health equity and transplant outcomes.

Reducing the duration of immune suppression

PTCy-based regimens, such as PTCy paired with tacrolimus and mycophenolate mofetil, permit the efficient and early taper of immune suppression. Several years ago, patients could remain on immune suppression for months or even years, with unsuccessful or choppy patterns in tapering GVHD prophylaxis. With PTCy-based regimens, we aim to start the immune suppression taper by two to three months post-transplant, with patients off by four to six months post-transplant. This limited exposure to immune suppression greatly reduces the overall burden of infections and risk for relapse. This approach also allows a smooth, and likely earlier, handoff to the referring oncologist to assist us with managing post-transplant maintenance, where appropriate, to reduce relapse risk.

Generally, PTCy-based GVHD prophylaxis is highly effective, facilitates early discontinuation of immune suppression, and facilitates the integration of post-transplant maintenance therapy. In a sense, PTCy mediates safe and effective passage for patients through the early post-transplant course to help them return home in a timely manner and enhance quality of life.

The ultimate goal for our allogeneic transplant patients is to be cured of the malignancy, successfully discontinue immune suppression, and return to the care of their referring oncologist and primary care team well by their two-year post-transplant anniversary.

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"The toolbox is quite full, so a lot of the research has been aimed at better understanding how epilepsy occurs and what drives that. A lot of that is currently is focused in the genetic area, where a tremendous amount of progress has been in the diagnosis of genetic epilepsies."

The care paradigm for patients with epilepsy has advanced significantly over the years, led by an expansion in the number of antiseizure medications (ASMs) and an increased awareness towards lifestyle modifications. Treating seizures requires a balanced approach of both pharmacological and nonpharmacological choices to truly make a difference. In some cases, despite numerous treatment attempts, a patient may still experience significant seizure activity.

In the past decade, the treatment standards for epilepsy have been raised. Nowadays, clinical trials assessing potential agents have begun to incorporate seizure reduction rate goals of 75% and 100%, rather than the traditional 50%, in an effort to demonstrate a next level of seizure control. Additionally, research has uncovered several prevention tactics to lower seizure rates, such as avoiding alcohol consumption, stress management, maintaining sleep, and eating meals at consistent times. Adherence to a treatment regimen has also been shown to have an impact on the frequency of seizures.

As more has been uncovered about the origins of epilepsy, the conversation has shifted to not just treating seizures, but preventing the disorder itself. To learn more about the recent progress in this field and how its changing care, NeurologyLive sat down with William Gallentine, DO, interim chief of pediatric neurology at Stanford Medicine Childrens Health. Gallentine discussed how research in genetic epilepsies and understanding the root cause of seizures has propelled the field forward and changed the quality of life for patients with these disorders. Furthermore, he spoke on the potential of gene therapy and the steps needed to take before therapies are available to potential patients.

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New Frontiers in the Prevention of Seizures, Gene Therapy in ... - Neurology Live

David R. Wise, MD, PhD, assistant professor, Department of Medicine, Department of Urology, NYU Grossman School of Medicine, director, Genitourinary Medical Oncology, NYU Langone Healths Perlmutter Cancer Center, NYU Langone Health, discusses the importance of germline and somatic testing in patients with metastatic castration-resistant prostate cancer (mCRPC), and the need for improved testing practices in clinical practice.

There are currently substantial gaps in the implementation of both hereditary and somatic testing for patients with mCRPC, despite efforts to increase the use of these tools in the clinic, Wise begins. Accordingly, it is essential to identify those who would most benefit from genetic testing in these patients, he says. This population includes men with metastatic disease, high-risk localized disease, and a significant family history of prostate cancer, Wise details. Patients of Ashkenazi Jewish descent, and those with a Gleason score of 6 or higher should also undergo hereditary testing, he adds.

More broad and consistent use of genetic testing could also improve the identification of individuals who harbor BRCA2mutations, Wise continues. However, only half of BRCA2 mutations in patients with prostate cancer can be attributed to hereditary predisposition, Wise says, explaining that the remaining half arise as new somatic mutations in the tumor alone. Accordingly, concurrent genetic and somatic testing is crucial to accurately identifying these mutations, he says.

The integration of both hereditary and somatic testing is essential to harnessing the full potential of precision medicine, ensuring that individuals with prostate cancer receive tailored treatments based on their unique genetic profiles, Wise continues. In particular, patients with BRCA2 mutations and similar homologous recombination repair alterations may benefit from the use of PARP inhibitors, Wise states. This drug class has emerged as a promising intervention in this space and have thus far demonstrated anti-tumor activity in this population, Wise concludes.

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In this retrospective analysis of blood cell counts and ratios, as easily detectable pro-inflammatory parameters, MLR and NLR at baseline were shown as independent predictive marker usable for therapy guidance in mBC patients to receive CDK4/6i plus ET. CDK4/6i treated patients with high MLR at baseline were significantly more likely to achieve no clinical benefit, indicating progressive disease within the first six months of therapy. Moreover, the prognostic value of MLR and NLR at baseline with regard to having a shorter OS was shown for patients receiving CDK4/6i as first line therapy after diagnosis of metastasis.

By comparison of matched samples at baseline and after four weeks of therapy, a significant decrease of neutrophils, monocyctes, platelets, leukocytes, lymphocytes, eosinophils as well as MLR and NLR under CDK4/6i was detected. In contrast, MCV increased in the majority of patients under therapy.

While decreasing PLR and increasing MCV within the first cycle of CDK4/6i correlated with shorter PFS, decreasing MLR within the first cycle was only correlated with a shorter PFS in the 1L CDK4/6i treated patients. These early-on-treatment assessments could be used as monitoring marker for therapy success.

Standard-of-care first-line therapy for patients with HR+/HER2- mBC without visceral crisis is CDK4/6i combined with ET, resulting in substantial PFS and OS benefits as well as maintained quality of life compared to ET alone7,8. HR+/HER2- mBC patients with visceral crisis receive chemotherapy as standard-of-care7. However, it is to question whether some patients without visceral crisis would benefit from chemotherapy more than from CDK4/6i plus ET. Although a meta-analysis revealed that no chemotherapy regimen showed increased PFS compared to CDK4/6i plus ET33, the Pearl study did not show superiority in PFS of Palbociclib+Fulvestrant vs. Xeloda34. Presented as an abstract, the Right Choice study further postulated that first-line Ribociclib plus ET increased PFS from 12.3months to 24.0months compared to chemotherapy in a patient cohort that included more than 50% of patients with visceral crisis35. These two studies question the standard-of-care and highlight the importance of individual factors that mediate the outcome under CDK4/6i.

At the moment, research focusses on these kind of individual factors as predictive markers to indicate de novo resistance to CDK4/6i therapy36. Predictive markers would enable individualized therapy approaches towards longer PFS, spared side effects and increased quality of life.

One of the factors that might influence the outcome of CDK4/6i is the composition of the tumor microenvironment37, because CDK4/6i was shown to effect the immune system. CDK4/6i triggers anti-tumor immunity by different ways. CDK4/6i activates tumor cell expression of endogenous retroviral elements, thus, increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and enhances tumor antigen presentation28. Enhanced tumor antigen presentation leads to increased anti-tumor immunity due to detection and killing of tumor cells by cytotoxic T cells. Second, the cytotoxic T cells themselves are also effected by CDK6 inhibition as it leads to de-repression of NFAT family transcription factors and consequently, increased cytotoxic T cell recruitment and enhanced T cell activation29. Both effects lead to cytotoxic T cell-mediated clearance of tumor cells. Third, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells (Tregs) by reduced activity of the E2F target, DNA methyltransferase28. Consequently, the number of pro-tumorigenic Tregs decrease. In summary, CDK4/6 inhibitors decrease Treg proliferation but increase tumor infiltration and activation of cyctotoxic T cells leading to an overall enhanced anti-tumor immunity. Fourth, CDK4/6i also leads to reduced stem cell and progenitor cell proliferation mediated by reduced Notch signaling30. A consequence of these CDK4/6i effects might be the long-term reduction in different blood cell populations and the common adverse events like neutropenia and leukopenia.

With the knowledge of the numerous effects of CDK4/6i therapy on tumor cells, Tregs, cytotoxic T cells, and even stem and progenitor cells, it is reasonable to assume that the pretreatment status of the tumor immunity may have predictive value. NLR, MLR and PLR are pro-inflammatory signatures representing peripheral blood surrogates of the tumor immunity.

Comparison of the descriptive statistics of all blood parameters at baseline in the entire HR+/HER2- mBC cohort to the healthy donor reference ranges according to Wakeman et al.32 showed the minimal and maximal values of the entire HR+/HER2- mBC cohort within the healthy reference range for lymphocyctes, eosinophils and basophils. In contrast, in the entire HR+/HER2- mBC cohort, minimal and/or maximal values for neutrophils, monocyctes, platelets, leukocytes and MCV were outside the healthy reference range. The mean values of all mentioned eight blood parameters of the entire HR+/HER2- mBC cohort at baseline were within the healthy reference range.

We identified high MLR at baseline as independent predictive factor for reduced PFS in the CDK4/6i cohort and decreasing MLR within the first four weeks under therapy was associated with poor PFS in the CDK4/6i 1L cohort. To our knowledge, MLR has not been examined as predictive marker for CDK4/6i by any other group before. It is further to notice that we used a similar cut-off as other groups that studied MLR in mBC patients including all BC subtypes (0.36 in this project; 0.3438 and 0.2839).

In a mouse model representing lung metastases in the BC setting, it was shown that circulating monocyctes were reduced in number under CDK4/6i, but an increase in monocyte invasion was detected40. The decrease in circulating monocyte number was detected in CDK4/6i patients in our project as well.

A meta-analysis revealed that the NLR cut-off values in 15 analyzed studies ranged from 1.9 to 5.041. The mean NLR value of 2.98, used in our entire cohort as cut-off, is in line with the majority of other studies that used 3.0 as cut-off41, further justified in one study as the optimal value to differentiate mBC patients with OS less or greater than 24 months38.

We identified high NLR at baseline as an independent predictive marker for shorter PFS in the CDK4/6i cohort. These results confirm the results shown recently as conference abstract, where high NLR at baseline was independently associated with lower PFS in 308 HR+/HER2- advanced BC patients receiving CDK4/6i therapy42. Similar results were demonstrated in a more stringent cohort of 126 1L CDK4/6i patients with a NLR cut-off of 2.5343. In a smaller cohort of 89 1L CDK4/6 treated HR+/HER2- mBC patients, high NLR (here defined>3.7) was not found to be significantly correlated with worse PFS in a meeting abstract44. The latter two studies highlight the importance of evaluating markers in a large stringent cohort and only the use of consistent cut-off values will lead to reproducible results transferable into clinical practise. However, the evidence of high NLR at baseline as predictive marker for PFS under CDK4/6i therapy accumulates and might, thus, be usable to identify patients with de novo resistance to CDK4/6i due to the pretreatment status of the tumor immunity detected by blood surrogates.

In our study, we included a control cohort only receiving ET and found no significant lower PFS in patients with high NLR at baseline. However, in the entire cohort, including CDK4/6i treated and only endocrine treated patients, univariate Cox regression showed a significant association of high NLR with worse PFS, questioning the specificity of NLR with regard to the given therapy as predictive marker for CDK4/6i. Similarly, the results of two studies analyzing eribulin treated mBC patients also suggested high NLR to be a predictive marker for shorter PFS in mBC receiving other treatment regimens than CDK4/6i22,45.

In this regard, it is to mention that clinical parameters influencing PFS should be integrated in the identification of a predictive marker, as done in this study by multivariate Cox regression analysis with clinical parameters also used in other CDK4/6i studies46,47. This is important because in a cohort of 263 mBC patients including all BC subtypes, a high NLR (defined as>2.32) was significantly associated with worse PFS in univariate Cox regression but not in multivariate Cox regression analysis48.

Interestingly, Kim et al. determined NLR after one treatment cycle with high NLR to predict a reduced PFS49,50. However, this strategy is not usable for therapy decision making, because a predictive marker has to be evaluated before therapy start.

In addition to the predictive value of NLR, we and others43 showed a significant correlation of high NLR at baseline with shorter OS in the 1L CDK4/6i cohort, demonstrating the prognostic value of NLR.

Decreasing PLR from baseline to four weeks of therapy correlated with a shorter PFS and OS in the CDK4/6i cohort identifying PLR dynamics as a potential monitoring and prognostic marker.

PLR, not PLR dynamics, correlated with worse OS in a huge cohort of 2374 BC patients, using a cut off value>30051. However, this group found high PLR not related to OS when analyzing only the luminal BC patients, which is in line with our results, since baseline PLR values in our luminal mBC patients before CDK4/6i showed no prognostic value.

Zattarin et al., described in a conference abstract that PLR at baseline and also after the first three treatment cycles related to worse PFS in 308 HR+/HER2- advanced BC patients receiving CDK4/6i42 while Weiner et al., presented in a meeting abstract a significant association between PLR at baseline and PFS using univariate und multivariate analysis in a more stringent cohort of 89 1L CDK4/6i treated CDK4/6 patients44. Both groups revealed a predictive value of PLR at baseline before CDK4/6i in mBC which we cannot confirm in our study.

Using an identical mean MCV value of 89.0fl at baseline as described before52, the rising MCV under CDK4/6i in our patients confirmed already published results52,55,56. In contrast to the results of the other workgroups, our resultsshowed a prolonged PFS in patients with increasing MCV even in multivariate Cox regression analysis.

Despite the search for a predictive marker assessable at baseline for therapy decision making, we evaluated the dynamics of the blood cell counts and ratio under the first CDK4/6i cycle. NLR, MLR as well as the number of neutrophils, monocyctes, platelets, leukocytes, lymphocytes and eosinophils decreased significantly from baseline to four weeks under therapy. These dynamics might be explained by the CDK4/6i induced cell-cycle arrest in hematopoietic cells30 but also by the increased recruitment of cyctotoxic T cells29 as well as the proliferation repression of regulatory T cells28 by CDK4/6i which we can only speculate but not proof in this study.

In addition to the monitoring value of MCV shift under CDK4/6i, we here present the monitoring value of the MLR shift from baseline to four weeks under therapy in the 1L CDK4/6 cohort, that might also be used to identify therapy success during treatment. Furthermore, we detected a prognostic value of baseline MLR, NLR and PLR in the 1L CDK4/6 cohort suitable to assess the outcome early and adjust therapy management and follow-up care.

Since this was a retrospective study, time points of blood cell count analysis varied in a number of cases for baseline and four-week analysis. Consequently, especially the short-term effects of one therapy free week after CDK4/6i therapy at the end of each cycle could have influenced the blood results. Despite evaluating different blood cell counts and ratios, detailed analysis of other inflammatory markers, eg. C-reactive protein, procalcitonin or other acute-phase proteins and Lactate dehydrogenase should also be taken into account in future studies. Unfortunately, these protein quantities were not available for our patients. Acute or chronic inflammatory diseases and/or cortison, novalgin or non-steroidal anti-inflammatory drug etc. intake was not documented for the included patients. Further prospective studies using fresh blood at the given time points would also allow for the quantification of B cells and T cells or the CD4+/CD8+cell ratio.

Although limited in sample size and not randomized for different treatment regimens, one advantage of our study is a control group to identify CDK4/6i specificity within our findings. To the best of our knowledge, this is the first study which included a control group to clearly identify CDK4/6i therapy specific predictive markers. One further advantage of this study are clearly defined sampling time points independent of dose reduction and drug holiday, which only take place after more than one therapy cycle.

We included patients that received CDK4/6i in the first line as well as in second or more lines, thus, the results of the latter group have to be interpreted with caution due to unknown effects of prior therapies on blood cell counts. The majority of patients (29/33) in the2L CDK4/6i received Palbociclib plus ET and only four patients in this cohort received Ribociclib plus ET, thus, results obtained for patients with2L CDK4/6i may be related more to Palbociclib then Ribociclib. However, our subgroup stratification clearly showed significances not only in the 1L CDK4/6i cohort, but also in the CDK4/6i cohort, consisting of 1L and2L CDK4/6i treated patients. Consequently, we here demonstrate a broader range of implications for the clinical setting as our results are not specific for the number of therapy lines applied before start of CDK4/6i therapy, but can be applied to the entire HR+/HER2- mBC population receiving CDK4/6i. As we differentiated the 1L CDK4/6i cohort from the2L cohort for the statistical analysis, reported 1L cohort results are as stringent as in other studies that only analyzed 1L CDK4/6i patients. The subgroup stratification into 1L and2L CDK4/6i recently gained relevance with the publication of the SONIA trial results that challenged the need of CDK4/6i in the 1L57.

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Ratios of monocytes and neutrophils to lymphocytes in the blood ... - Nature.com