On June 4, 2021, Caladrius Biosciences, Inc., a Delaware corporation (the "Company"), reported that it entered into an At The Market Offering Agreement, dated June 4, 2021 (the "ATM Agreement") with H.C. Wainwright & Co., LLC ("Wainwright"), as sales agent, in connection with an "at the market offering" under which the Company from time to time may offer and sell shares of its common stock, par value $0.001 per share (the "Common Stock"), having an aggregate offering price of up to $50,000,000 (the "Shares") (Filing, 8-K, Caladrius Biosciences, JUN 4, 2021, View Source [SID1234583632]). Shares sold under the ATM Agreement will be offered and sold pursuant to the Company’s Registration Statement on Form S-3, which was initially filed on April 1, 2021 and which was declared effective by the Securities and Exchange Commission (the "SEC") on May 4, 2021 (Registration No. 333-254971) (the "Registration Statement") and a prospectus supplement that the Company expects to file with the SEC relating to the Shares shortly after the filing of this Current Report on Form 8-K.

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This Current Report on Form 8-K shall not constitute an offer to sell or the solicitation of an offer to buy the Shares, nor shall there be any offer, solicitation or sale of the Shares in any state or country in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or country.

The opinion of the Company’s counsel regarding the validity of the Shares is filed as Exhibit 5.1 to this Current Report on Form 8-K. This opinion is also filed with reference to, and is hereby incorporated by reference into, the Registration Statement.

The Company cautions you that statements included in this Current Report on Form 8-K that are not a description of historical facts are forward-looking statements. These forward-looking statements include statements regarding the Company’s ability to sell Shares pursuant to the ATM Agreement. The inclusion of forward-looking statements should not be regarded as a representation by the Company that any of these statements, results or sales will be achieved or completed due in part to risks and uncertainties inherent in the Company’s business, including those described in the Company’s Form 10-K for the year ended December 31, 2020 filed with the SEC on February 25, 2021. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and the Company undertakes no obligation to revise or update this report to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.

On June 4, 2021 SQZ Biotechnologies Company (NYSE: SQZ), focused on unlocking the full potential of cell therapies for multiple therapeutic areas, reported initial results from its ongoing Phase 1 clinical trial of SQZ-PBMC-HPV demonstrating that the investigational cell therapy is safe and well-tolerated and can stimulate immune responses in certain patients with advanced or metastatic Human Papillomavirus positive (HPV16+) tumors (Press release, SQZ Biotech, JUN 4, 2021, View Source [SID1234583627]). The trial also showed that the company’s clinical stage manufacturing process of its autologous cell therapy is fast and reliable. The monotherapy stage trial data of the company’s first Antigen Presenting Cell (APC) platform candidate was presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting; poster presentation 2536.

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"Our vision is to make cell therapies that are safe and available with rapid turnaround times, allowing access to patients who need them," said Oliver Rosen, M.D., chief medical officer at SQZ Biotechnologies. "The company’s first-in-human data of a cell-based therapeutic vaccine are encouraging and an important first step towards validation of our directed immunity approach. Within this small trial of patients with very advanced disease, four patients who had progressed after multiple prior therapies achieved stable disease. These early outcomes, combined with encouraging safety data and fast clinical-scale manufacturing times, support our plans to initiate the trial’s safety combination phase with immune checkpoint inhibitors."

Safety & Tolerability

A primary outcome measure in the monotherapy dose escalation phase of the trial is safety and tolerability. Findings from the trial show that SQZ-PBMC-HPV was safe and well-tolerated at all tested dose levels with patients receiving 2 to 10 doses. No dose-limiting toxicities were observed.

"Overall, SQZ-PBMC-HPV has been safe and well tolerated by patients, even advanced patients as we have seen in this study," said study author Antonio Jimeno, M.D., Ph.D., Professor of Medicine, Oncology and Otolaryngology, University of Colorado School of Medicine, and Co-Leader, Development Therapeutics Program, University of Colorado Cancer Center. "I look forward to completing the single agent portion of the trial and advancing into the combinations of SQZ-PBMC-HPV with immunotherapies."

There were no grade 3 or higher treatment related serious adverse events (SAEs). In one patient, a grade 2 cytokine release syndrome and immune-related reaction was observed. A related grade 3 adverse event (AE, anemia) was observed in another patient.

Manufacturability

Manufacturing feasibility is a secondary outcome measure in the monotherapy phase of the trial. All patient batches were produced under current good manufacturing practice regulations, met specifications, and yielded multiple cryopreserved doses in less than 24 hours.

The findings show that doses of SQZ-PBMC-HPV were released and available for administration approximately one week from the time a patient’s cells were drawn. Antigen presentation was confirmed in all patient batches independent of individual patient medical history or prognostic score.

Patient Characteristics & Immune Response Biomarkers

The clinical trial enrolled patients with HPV16+ cancers progressing after unlimited prior lines of therapy. The 12 enrolled patients had very advanced disease:

Median number of prior cancer treatments was four with one patient having received seven prior treatments

Eleven patients previously treated with an immune checkpoint inhibitor (ICI)

Six of the 12 patients had a Royal Marsden Hospital (RMH) score of 2. (RMH scores range from 0-to-3, with scores of 2 and higher predicting poor prognosis and short life expectancy)

Despite the treatment refractory status of the enrolled patients, 4 out of 6 patients with RMH scores less than 2, reflecting less advanced disease, achieved stable disease as best overall response. Two of these patients showed an increase in CD8 tumor infiltrating lymphocytes (TILs), an important biomarker in immune-oncology therapy development.

The study authors highlighted two patients – Patients 2 and 7 detailed below – which suggested that less advanced patients with lower tumor burden, such as patient two, might have a higher likelihood of clinical benefit.

Patient 2: Enrolled 3-and-half years after diagnosis and had a best overall response of progressive disease with ICI therapy. The patient had an RMH score of 1 and low tumor burden. She achieved stable disease while on the SQZ-PBMC-HPV-101 trial and remained on study for over 10 months. Image analysis of the central tumor 28 days after the first dose showed a 2-fold increase in CD8 TILs on treatment compared to baseline

Patient 7: Enrolled 1 year after diagnosis and had a partial response with chemotherapy in combination with ICI therapy but then progressed. He achieved stable disease after treatment on the SQZ-PBMC-HPV-101 trial and remained on study for three months. Image analysis of the central tumor showed a 6-fold increase in CD8 TILs on treatment compared to baseline

The company is now actively enrolling patients in the last monotherapy highest-dose cohort of the Phase 1 trial. These results will inform the dosage approach for the combination therapy phase of the clinical trial with immune checkpoint inhibitors.

Poster Presentation Details

Title: Initial Results of a first-in-human, dose escalation study of a cell-based vaccine in HLA-A* 02+ patients with recurrent, locally advanced or metastatic HPV16+ solid tumors

First Author: Antonio Jimeno, M.D., Ph.D., University of Colorado Cancer Center

Abstract Number: 2536

Poster Session: Developmental Therapeutics — Immunotherapy

Date and Time: A copy of the poster is available on-demand via the ASCO (Free ASCO Whitepaper) virtual meeting website.

SQZ-PBMC-HPV-101 Trial Design

SQZ-PBMC-HPV is being evaluated in a Phase 1 clinical trial for the treatment of HPV16+ advanced or metastatic solid tumors. Patients must be positive for the human leukocyte antigen serotype HLA-A*02. The investigational candidate, which targets E6 and E7 oncoproteins, is being studied as a monotherapy and in combination with immuno-oncology agents. The study’s primary outcome measures in the monotherapy and combination phases of the trial include safety and tolerability. Antitumor activity is a secondary outcome measure in both the monotherapy and combination stages of the trial, and manufacturing feasibility is a secondary outcome measure in the monotherapy phase of the trial. The monotherapy phase of the study includes escalating dose cohorts with a DLT window of 28 days and the definition of a recommended phase 2 dose. The planned safety combination phase of the study will include SQZ-PBMC-HPV and checkpoint inhibitors that have previously received regulatory approval. DLT will be measured over 42 days in the safety combination phase.

About Human Papillomavirus Positive Cancers

Human papillomavirus (HPV) is one of the most common viruses worldwide and certain strains persist for many years leading to cancer. According to the Centers for Disease Control (CDC), in the United States HPV+ tumors represent 3% of all cancers in women and 2% of all cancers in men, resulting in over 39,000 new cases of HPV+ tumors every year. HPV infection is larger outside of the U.S., and according to the International Journal of Cancer HPV+ tumors account for 4.5% of all cancers worldwide, resulting in approximately 630,000 new cases every year. According to the CDC, HPV infection plays a significant role in the formation of more than 90% of anal and cervical cancers, and most cases of vaginal (75%), oropharyngeal (70%), vulval (70%) and penile (60%) cancers.

On June 4, 2021 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing a novel class of T cell engagers, reported a pipeline update on its four clinical stage programs, including updating the interim data presented earlier at ASCO (Free ASCO Whitepaper) from the ongoing dose escalation portion of the Phase 1/2a trial for HPN424 in patients with metastatic castration resistant prostate cancer (mCRPC) (Press release, Harpoon Therapeutics, JUN 4, 2021, View Source [SID1234583615]). Harpoon has four product candidates in clinical trials that are based on its proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells.

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"We are excited by the clinical data emerging from our four TriTAC programs that are showing tumor size reductions or stable disease, meaningful treatment duration, clinical activity, target engagement, extended half-life, and manageable safety and tolerability profiles in the heavily pretreated patient populations," stated Jerry McMahon, Ph.D., President and CEO, Harpoon Therapeutics. "As we continue to advance to higher doses in each of these programs, we look forward to the initiation of expansion cohorts this year."

"The clinical signals observed in the HPN424 trial and the unconfirmed partial response in the recently initiated HPN328 trial are very encouraging," said Natalie Sacks, M.D., Chief Medical Officer of Harpoon. "Looking across the portfolio, we are encouraged by how our novel technology is performing across multiple tumor types. We are seeing initial signs of clinical activity while effectively managing cytokine-mediated adverse events."

Dose escalation and step dosing for HPN424 Phase 1/2a clinical trial continuing.
As of May 31, 2021, the data cutoff date for the Company’s HPN424 presentation, the Company updated the ASCO (Free ASCO Whitepaper) interim data to describe newly enrolled patients and additional follow-up on existing patients already enrolled in the 300 ng/kg step dose cohort. The company has examined several step dosing regimens in this cohort and had the following observations:

Eight patients most recently enrolled in this cohort were treated with the same modified step dose regimen. Preliminary data from these patients include 3/8 (38%) with PSA declines that occur early in the course of treatment.

For the total 19 patients enrolled in this cohort, 4/19 showed PSA declines, including two patients with PSA30.
The ASCO (Free ASCO Whitepaper) poster presentation, included the following observations:

Antitumor activity includes a confirmed PR per RECIST, PSA declines and CTC reductions.
Fifteen of 74 (20%) pts with >1 post-baseline value had PSA decreases from baseline ranging from -2% to -76%, including 4 pts with PSA50 response and 2 pts with PSA30 response
Treatment duration > 24 weeks observed in 15 of 74 (20%) pts, including 8 of 17 (47%) chemo-naïve patients
Reduction in CTCs was seen in 36 of 64 (56%) patients with available baseline and on-treatment CTC counts
CRS has been transient and manageable with 4% of patients experiencing Grade 3 CRS
CRS and transaminitis events observed most often in Cycle 1, with diminished frequency and severity in subsequent cycles
Introduction of step dose regimens has allowed for the administration of higher target doses, currently at 300ng/kg
HPN536 (mesothelin TriTAC) Phase 1/2a clinical trial continues dose escalation. Dosing has occurred across 10 fixed-dose cohorts of 6 to 560ng/kg and three step dose cohort up to 1200ng/kg, with total enrollment of 60 patients. Tumor types treated include late-stage ovarian (47%), pancreatic (40%) and peritoneal and pleural mesothelioma (13%) cancers. Pharmacokinetic analysis shows median half-life of more than 70 hours for HPN536. Among the relapsed/refractory ovarian cancer patients with at least one post-baseline scan, 11 of 20 (55%) patients showed stability of target lesions, including three patients with target lesion shrinkage. In addition, five of 27 (19%) ovarian cancer patients had a duration of treatment of greater than 24 weeks. As of May 31, 2021, MTD has not been reached. The Company expects to present interim data at a medical conference in 2021.

Dose escalation for HPN217 (BCMA TriTAC) Phase 1/2 clinical trial making good progress. Relapsed/refractory multiple myeloma patients (N=20) have been treated across eight fixed dose cohorts of 5 to 2150 µg weekly, reflecting rapid dose expansion since the trial began. HPN217 has been well tolerated, and no DLTs have been observed as of the May 10, 2021 cutoff date. Pharmacokinetic analysis shows half-life extension to support at least once weekly dosing. A presentation of interim data is anticipated as well as initiation of a dose expansion cohort in the second half of 2021.

Dose escalation for HPN328 (DLL3 TriTAC) Phase 1/2 clinical trial initiated in late 2020 and has shown rapid progress. The first single patient cohort began with a flat dose of 15µg of HPN328 administered once weekly by intravenous infusion and has proceeded to the fourth cohort at a dose of 405µg. Eligible patients include small cell lung cancer patients who have relapsed after platinum chemotherapy and patients with other tumors associated with DLL3 expression. An unconfirmed partial response has been observed for one patient with small cell lung cancer from the 45µg dose cohort. Presentation of initial interim data is planned for the second half of 2021.

IND-enabling studies for HPN601 (EpCAM ProTriTAC) are progressing as planned. HPN601 is a conditionally active T cell engager based on the ProTriTAC platform. EpCAM is expressed in a broad range of solid tumors, including gastrointestinal cancers, potentially enabling HPN601 to address multiple indications with high unmet medical need.

Conference Call and Webcast Today

Harpoon’s management will host a webcast and conference call at 4 p.m. ET / 1 p.m. PT on Friday, June 4, 2021 to review the data presented at ASCO (Free ASCO Whitepaper) and provide an update on its other pipeline programs. The live call may be accessed by dialing 866-951-6894 for domestic callers or 409-216-0624 for international callers and using conference ID # 2657278.

A live webcast of the call will be available from the Events and Presentations section of the company’s website at View Source and will be archived there shortly after the live event.

On June 4, 2021 Bayer reported that it is presenting study results at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting being held online June 4-8, 2021 (Press release, Bayer, JUN 4, 2021, View Source [SID1234583613]).

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In particular, Bayer is presenting four abstracts related to its Vitrakvi (larotrectinib) across TRK fusion cancer patients of all ages, ranging from 0.1 to 84 years, and for multiple tumor types. Vitrakvi is a first-in-class TRK inhibitor for TRK and presenters are supporting the drug’s effectiveness in a range of cancers with TRK gene fusions regardless of tissue type or patient age.

Scott Fields, Head Senior Vice President, Oncology Development, Bayer Global, and Hendrik Nogai, Vice President, Global Development Lead NTRK Program, SBU Oncology, Bayer, took time out ahead of ASCO (Free ASCO Whitepaper) to speak with BioSpace about the drug and the upcoming presentations.

The four specific presentations look at long-term efficacy and safety of the drug in an integrated dataset of TRK fusion cancer patients; long-term results of the drug in patients with TRK fusion lung cancer; intra-patient comparison of Vitrakvi clinical trials in TRK fusion cancer, which is an expanded dataset; and results of the drug in adults and children with TRK fusion-positive primary tumors of the central nervous system.

Fields emphasizes that Vitrakvi is not tissue specific, but works on a particular type of gene fusion known as neurotrophic receptor tyrosine kinase (NTRK), or just TRK. It received accelerated approval from the U.S. Food and Drug Administration (FDA). With the accelerated approval pathway, drugs for serious conditions that fill an unmet medical need can be approved based on a surrogate endpoint, which allows them to get on the market faster. That surrogate endpoint is often a laboratory measurement, radiographic imagine, physical sign or other measure that is believed to predict clinical benefit but is not by itself a measure of clinical benefit. Then, the company continues to conduct studies to verify the drug’s efficacy and safety.

"TRK fusion cancers can come from the liver, they can come from the pancreas, they can come from the brain. It’s more about the mutation," Fields said. "It’s not about which tissue it comes from. And this is the first time ever that a tumor has been defined by a mutation, not by the histologic tissue. It drives the cancer. And when we block it with Vitrakvi, you see responses that are really quite extraordinary."

For example, the studies they are presenting indicate a 75% overall response rate (ORR) that is very durable. Fields says the overall survival time "hasn’t even been reached at forty-nine months."

The expanded data has a longer follow-up with 206 adult and pediatric patients that could be evaluated. They had TRK fusion cancer across 21 different tumor types. Out of that 75% ORR, 22% were complete responses. For the patients with brain metastases, the ORR was 73%. The median duration of response (DoR) was 49.3 months at a median follow-up of 22.3 months.

"We not only confirmed the data, but even seemed to improve on it," Nogai said. "So we see longer durability of the responses and the responses rate is even increasing with time."

The 22% complete responses in solid tumors, Nogai added, "is quite remarkable, and with the long follow-up, we have a median duration of response of 49 months. This is almost unheard of."

The additional data also suggests a very good safety profile, even though "the patients may remain on treatment for many years," according to Nogai.

One of the presentations also shows the drug’s activity in patients with central nervous system metastases. The data presented includes an updated and extended retrospective growth modulation index (GMI) analysis limited to patients enrolled in Vitrakvi trials with at least one previous line of therapy. GMI is a retrospective intra-patient comparison that utilizes the patient as their own control by comparing PFS on current therapy to time to progress or treatment failure (TTP) on the most recent previous therapy.

"This was one area of uncertainty. We did not have a lot of patients with CNS disease. But now, with the expanded dataset, we can see that it is an active drug," Nogai said.

Updated data with a cut-off of July 20, 2020, is being presented on heavily pre-treated adult patients with TRK fusion with lung cancer. The patients received a median of three previous therapies. The data demonstrated the drug’s consistent response rates with longer follow-up.

"The response rate in these fifty patients is around 73% again," Nogai said. "Remarkable durability at 34 months in patients that is still ongoing, and with a PFS of 35 months."

Both Fields and Nogai emphasized that Vitrakvi is turning out to be effective in children and adults with TRK fusion cancers.

"We should mention that we do have a liquid formulation. So even the very, very young patients can receive this, as well as older patients," Fields said. "It’s very important to ensure that patients are getting tested for TRK fusions, because Vitrakvi is demonstrating really good activity in these patients across cancer types and different ages."

There are several ways to test for the gene fusions, with the most easy and affordable being immunohistochemistry (IHC), although there are also next-generation sequencing (NGS) tests and PCR as well, which are more expensive, and typically used for confirmation. The results of these studies present a strong argument for comprehensive genomic testing that includes NTRK 1/2/3 genes for patients, to better understand what is driving the cancer and to appropriately match them with the right treatment approach.

Fields notes, "This is an inexpensive way to look for patients, but it always has to be confirmed. NGS is the standard for confirmation but is quite expensive and not routinely performed. However, correct diagnosis is one of the most important things we’re doing. Doctors really need to be aware of this. You need the pediatric oncologist to understand it and the oncologists focused on adults or specific cancers. This drug represents a meaningful advancement in the treatment of both adult and pediatric patients with TRK fusion cancer, regardless of where they originate in the body."

On June 4, 2021 Veracyte, Inc. (Nasdaq: VCYT) reported that Medicare Administrative Contractors Palmetto GBA, WPS and CGS Administrators, LLC have finalized their coverage policies for Decipher Bladder, a genomic subtyping tool that helps physicians manage treatment decisions for patients with bladder cancer (Press release, Veracyte, JUN 4, 2021, View Source [SID1234583612]). These local coverage determinations (LCDs) make Decipher Bladder the first genomic test to be covered by Medicare for such patients. Developed through the Medicare MolDX program, the policies will become effective July 18, 2021, and provide a framework for other participating MACs to follow.

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Noridian Healthcare Solutions, another Medicare Administrative Contractor, is expected to similarly finalize its draft LCD, which will make Decipher Bladder a covered benefit for more than 62 million Medicare beneficiaries. In the United States, more than 80,000 individuals are diagnosed with bladder cancer annually, approximately 44,000 of which will have the non-metastatic, Stage I-IIIa disease indicated in these policies.

"Physicians treating patients with bladder cancer are faced with complex and potentially life-changing treatment decisions, including whether or not to prescribe neoadjuvant chemotherapy or proceed directly to radical cystectomy," said Tina Nova, Ph.D., Veracyte’s general manager, urologic cancers. "Studies have demonstrated that knowledge of an individual’s bladder-tumor molecular subtypes can help guide these decisions, over and above clinical features alone. The coverage decisions announced today will make it possible for physicians to access this critical genomic information."

The Decipher Bladder test is supported by multiple peer-reviewed clinical studies demonstrating its ability to identify which patients have a higher risk of upstaging to non-organ confined disease at surgery and which patients may benefit the most from neoadjuvant therapy. The test also can be used to identify neuroendocrine-like and immune-infiltrated subtypes, which may have implications for future therapeutic strategies.

About Decipher Bladder

Decipher Bladder is a genomic test that measures the molecular profile of bladder cancer using gene expression analysis from transurethral resected bladder tumor specimens. It was developed for bladder cancer patients with muscle-invasive disease who face the question of immediate cystectomy or systemic treatment in the neoadjuvant setting prior to cystectomy (NAC). The assay results are reported as one of five molecular subtypes (Luminal, Luminal-Infiltrated, Basal, Basal Claudin Low or Neuroendocrine-like), each of which has distinct biological composition, clinical behavior and predicted benefit from NAC.