Organoids Guide Treatment Decisions“

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] June 15, 2022 Brad Power “We design our drug panel so that it is comprehensive enough that we would be able to find at least one exceptional drug in the majority of cases.

” – Payel Chatterjee, SEngine Meeting Summary Payel Chatterjee, Chief Scientist, SEngine Precision Medicine, led a discussion on the role of organoids in guiding cancer treatment decisions.

The value proposition of “functional testing” (applying 100 or more drugs to fresh tumor tissue and seeing how the cancer responds) is that this very direct approach can identify unexpected drugs to try, and extraordinary results, for some patients.

The drugs in the panel that SEngine tests are unique because they pay attention to the genomics and FDA-approved drugs for that cancer, but also include drugs that have been approved for other cancers to make a very comprehensive list to test. This broader range of drug options leads to surprises every day.

The lesson from their experience is that you should never be too biased to the typical treatments because you don't know if a surprise might come up. Some of their surprises and successes have been in cancers with very difficult prognoses, such as pancreatic and ovarian cancer.

Payel shared several stories, including unexpected and exceptional responses: ●A pancreatic cancer patient with a HER2 amplification had an amazing response. For 1.5 years, they have been scanning her, and they can’t believe it, but there is no evidence of disease. ●A woman who was in hospice with a very late stage of ovarian cancer tried the SEngine organoid test.

The test indicated a top candidate of an approved drug that was normally indicated for a blood cancer, but not for her cancer. The doctors were surprised, but tried it, and she experienced an exceptional response. She was able to get out of hospice and travel. ●A very terminally ill cholangiocarcinoma patient had progressed through five lines of treatment, but nothing was working.

A SEngine organoid test identified Dasatinib, which was used mostly in leukemias, as a top drug. It had an exceptional response. The patient’s pain and tumor markers were controlled for several months when her life expectancy would've been measured in weeks. ●A colon cancer patient’s doctor was struggling to find a therapy after several lines of therapy.

SEngine PARIS test identified gemcitabine, which is a common chemotherapy. The patient took it, the tumor was reduced, and the patient lived for nine months, instead of weeks. ●A prostate cancer patient had failed four lines of treatment. SEngine identified 9 drugs with relatively high scores, showing potential. The patient chose Azacitidine because he learned it had fewer side effects.

Organoids maintain the tumor heterogeneity and physiology.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] 43 drugs can be tested on a full plate, drawn from physician rec

f treatment. SEngine identified 9 drugs with relatively high scores, showing potential. The patient chose Azacitidine because he learned it had fewer side effects. Organoids maintain the tumor heterogeneity and physiology.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] 43 drugs can be tested on a full plate, drawn from physician recommendations, the standard of care, the genomic landscape, and FDA-approved drugs, to create a comprehensive targetable list.

In 70% of cases, including patients who have had multiple lines of therapy and have no known druggable biomarkers, SEngine could still identify an actionable candidate therapy, beyond the patient’s genomic report. Questions for Further Discussion ●Functional testing seems like it offers useful information to guide complex treatment decisions and may uncover unexpected treatment candidates.

Do you agree? ●How can we accelerate adoption? What are the barriers to wider use?

The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] — Meeting Notes Brad Power: Payel Chatterjee of SEngine will be leading a discussion on using organoids to guide cancer treatment decisions. Payel Chatterjee: I'm the principal scientist at SEngine, where I manage drug selection and reporting for the PARIS test.

My presentation will be about personalizing cancer treatment with the PARIS test for solid tumors. The name Paris comes from mythology – Paris killed Achilles by shooting him in his heel because that's the place Achilles was most vulnerable.

That's the concept of SEngine Precision Medicine: finding the unique vulnerabilities of every patient's tumor so that we can target and treat the patient with those unique drugs.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] Even though there have been advancements through DNA sequencing or through FDA- approved therapies or different treatment approaches, like the proton beam or Gamma Knife, we still lose a lot of people every year from this disease. A lot more still has to be done.

We believe that every individual's cancer is a unique mosaic of molecular changes.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] fusions, or maybe some other mutations, but every patient's tumor, no matter which type of

ores, showing potential. The patient chose Azacitidine because he learned it had fewer side effects. Organoids maintain the tumor heterogeneity and physiology.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] 43 drugs can be tested on a full plate, drawn from physician recommendations, the standard of care, the genomic landscape, and FDA-approved drugs, to create a comprehensive targetable list.

In 70% of cases, including patients who have had multiple lines of therapy and have no known druggable biomarkers, SEngine could still identify an actionable candidate therapy, beyond the patient’s genomic report. Questions for Further Discussion ●Functional testing seems like it offers useful information to guide complex treatment decisions and may uncover unexpected treatment candidates.

Do you agree? ●How can we accelerate adoption? What are the barriers to wider use?

The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] — Meeting Notes Brad Power: Payel Chatterjee of SEngine will be leading a discussion on using organoids to guide cancer treatment decisions. Payel Chatterjee: I'm the principal scientist at SEngine, where I manage drug selection and reporting for the PARIS test.

My presentation will be about personalizing cancer treatment with the PARIS test for solid tumors. The name Paris comes from mythology – Paris killed Achilles by shooting him in his heel because that's the place Achilles was most vulnerable.

That's the concept of SEngine Precision Medicine: finding the unique vulnerabilities of every patient's tumor so that we can target and treat the patient with those unique drugs.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] Even though there have been advancements through DNA sequencing or through FDA- approved therapies or different treatment approaches, like the proton beam or Gamma Knife, we still lose a lot of people every year from this disease. A lot more still has to be done.

We believe that every individual's cancer is a unique mosaic of molecular changes.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] fusions, or maybe some other mutations, but every patient's tumor, no matter which type of cancer we are looking at, always presents us with a unique constellation of genetic change

ges, either gene mutations, amplifications,

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] fusions, or maybe some other mutations, but every patient's tumor, no matter which type of cancer we are looking at, always presents us with a unique constellation of genetic changes. For example, if we see colorectal cancer with a KRAS mutation, no two patients are the same. We have seen KRAS mutations along with P53.

We have seen KRAS mutations with CDK12 and 2AB loss for prostate cancer. We have seen androgen amplification with a BRCA1 mutation, ATM, and other mutations. There are plenty of permutations and combinations of different genetic changes that make every individual's cancer almost like a unique disease. At SEngine our CEO and the chief scientific officer is Dr. Carla Grandori.

SEngine was founded based on scientific research that happened at the Fred Hutch Cancer Center. Our co-founders were principal investigators and professors at Fred Hutch. Besides Dr. Carla Grandori, they included Dr. Chris Kemp, Dr. VK Gadi, who is a breast cancer surgeon, and Dr. Eddie Mendez, whom we lost due to cancer, unfortunately, but his vision still continues through SEngine.

We grow tumor organoids in the lab, outside the body. We get the patient sample and grow it in the form of clumps of tumor cells in a 3D structure. We merge that with robotics technology for drug screening. We treat the organoids with drugs over six days. Then we merge this result with our unique bioinformatics technology. We rank all the drugs from 15 to one.

Every drug gets a unique proprietary score, which we call the “SPM score,” the SEngine Precision Medicine score. Our test is unique because it's a CLIA-certified, first-in-class, pan-cancer assay. It's a functional assay rather than a predictive assay. We test the drugs on which we are reporting.

We don't discriminate against patients based on their previous lines of therapy, meaning we have patients who have had multiple lines of therapy, even up to seven or eight lines of therapy.

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] We look for an exceptional drug for the patient. We provide a report to the oncologist which gives the drug sensitivity unique for that patient. We are CLIA-certified in all states except in New York State, where certification is pending. We are trying for insurance reimbursement.

It might still take a little over a year, but we are taking baby steps towards it. We are also involved in multiple clinical studies across the world. We have a clinical trial for colorectal cancer in France with Gustave Roussy, one of the leading cancer institutes there. We are part of two cholangiocarcinoma clinical trials at the University of Washington and University of Chicago.

inical trial for colorectal cancer in France with Gustave Roussy, one of the leading cancer institutes there. We are part of two cholangiocarcinoma clinical trials at the University of Washington and University of Chicago.

We are regular members of the University of Washington's gynecology and oncology departments’ tumor board, where we discuss with the doctor what might be the next step for the patient. We think our test is superior to DNA sequencing. Nowadays it's common practice that if a patient comes to the clinic, they will get genetic testing.

But only 18% of patients with a DNA sequencing get a drug prediction, while for us, at least 75% of patients get a drug prediction. For example, if a patient gets DNA sequencing, and BRCA1 or BRCA2 mutations are present, then the DNA sequencing can predict that a PARP inhibitor might be beneficial, but you don't know which PARP inhibitor would be beneficial.

There are four different PARP inhibitors. One might be better for a patient or for your tumor type or your stage of the disease, compared to the other three. We test all four along with an ATR inhibitor or platinum, and we can tell you which PARP inhibitor would be best for your tumor.

That gives the power and that cuts out the whole guessing game, because from the beginning you know which drug would be best for that patient's tumor. Rick Stanton: Is your testing limited to small molecules?

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] Payel Chatterjee: Currently we only do small molecules. We do both targeted therapies as well as chemotherapy. We don't do immunotherapy yet. That's in process. We just hired someone who has unique experience in immunotherapy and culturing immune cells with tumor cells. Same for monoclonal antibodies.

We have tried before for HER2 with trastuzumab (herceptin), but it's trickier to test it in an ex vivo or in vitro system. For prospective and retrospective concordance, we could predict a drug in almost 75 of percent of cases. We see a very high concordance with prospective studies, where the patient received a drug guided by the PARIS test.

We have also seen over 80% retrospective concordance for patients where the patient has seen a drug already and progressed on that drug. We could see that our SPM score would be very low for that drug.

We have also seen if a combination didn't work, for example, if FOLFOX (a combination chemotherapy regimen that includes the drugs FOLinic acid, Fluorouracil, and OXaliplatin) didn't work for the patient, we see either the Flu and FOL part, or the OX part, when tested separately, either both of them performed poorly, or at least one performed very poorly in our test.

And that's when you know the combination is not going to work. We see this very regularly across the tumor type, and we also do very rare tumor types. Before SEngine, I did prostate cancer research.

tes there. We are part of two cholangiocarcinoma clinical trials at the University of Washington and University of Chicago. We are regular members of the University of Washington's gynecology and oncology departments’ tumor board, where we discuss with the doctor what might be the next step for the patient. We think our test is superior to DNA sequencing.

Nowadays it's common practice that if a patient comes to the clinic, they will get genetic testing. But only 18% of patients with a DNA sequencing get a drug prediction, while for us, at least 75% of patients get a drug prediction.

For example, if a patient gets DNA sequencing, and BRCA1 or BRCA2 mutations are present, then the DNA sequencing can predict that a PARP inhibitor might be beneficial, but you don't know which PARP inhibitor would be beneficial. There are four different PARP inhibitors. One might be better for a patient or for your tumor type or your stage of the disease, compared to the other three.

We test all four along with an ATR inhibitor or platinum, and we can tell you which PARP inhibitor would be best for your tumor. That gives the power and that cuts out the whole guessing game, because from the beginning you know which drug would be best for that patient's tumor. Rick Stanton: Is your testing limited to small molecules?

‘Organoids Guide Treatment Decisions“ (Payel Chatterjee, SEngine) [#13] Payel Chatterjee: Currently we only do small molecules. We do both targeted therapies as well as chemotherapy. We don't do immunotherapy yet. That's in process. We just hired someone who has unique experience in immunotherapy and culturing immune cells with tumor cells. Same for monoclonal antibodies.

We have tried before for HER2 with trastuzumab (herceptin), but it's trickier to test it in an ex vivo or in vitro system. For prospective and retrospective concordance, we could predict a drug in almost 75 of percent of cases. We see a very high concordance with prospective studies, where the patient received a drug guided by the PARIS test.

We have also seen over 80% retrospective concordance for patients where the patient has seen a drug already and progressed on that drug. We could see that our SPM score would be very low for that drug.

We have also seen if a combination didn't work, for example, if FOLFOX (a combination chemotherapy regimen that includes the drugs FOLinic acid, Fluorouracil, and OXaliplatin) didn't work for the patient, we see either the Flu and FOL part, or the OX part, when tested separately, either both of them performed poorly, or at least one performed very poorly in our test.

And that's when you know the combination is not going to work. We see this very regularly across the tumor type, and we also do very rare tumor types. Before SEngine, I did prostate cancer research. Then after coming to SEngine, within two years I got exposed to so many different types of cancer that I never knew existed. We don't discriminate.