Epacadostat/ Nivolumab Combo Active in Melanoma, Head and Neck Cancer

Excerpt:

“Combining the IDO inhibitor epacadostat with nivolumab (Opdivo) demonstrated promising signs of activity for patients with squamous cell carcinoma of the head and neck (SCCHC) and those with melanoma, according to findings from the phase I/II ECHO-204 study presented at the 2017 ASCO Annual Meeting.

“The combination demonstrated an objective response rate (ORR) of 63% and a complete response (CR) rate of 5% for patients with treatment-naive melanoma, in the multi-arm, open-label trial. In those with SCCHC, the ORR was 23% and the CR rate was 3%. The combination was not effective in unselected patients with ovarian cancer and colorectal cancer (CRC).”

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If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.


In Bold Move, FDA Approves Cancer Drug For Any Advanced Tumor With Genetic Changes

Excerpt:

“For the first time, the FDA has approved a drug for use in cancer—of any type—that harbors certain molecular features. Merck’s Keytruda, an immune oncology drug, may be prescribed for any resistant, metastatic tumor with microsatellite instability (MSI) or other evidence for defective DNA mismatch repair.

“This is good news for patients. Previously, Keytruda (pembrolizumab) was approved by the FDA for use in some forms of lung cancer, melanoma, head and neck cancer, and Hodgkin’s lymphoma. Now, patients can try this medication if they have advanced cancer of any form with pathological MSI or DNA mismatch repair defects. Microsatellite instability most often appears in colon cancers, affecting around 15% of cases. Variants of DNA mismatch repair genes are implicated in heritable cancer dispositions such as Lynch syndrome.”

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If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.


Cancers Evade Immunotherapy by ‘Discarding the Evidence’ of Tumor-Specific Mutations

Excerpt:

“Results of an initial study of tumors from patients with lung cancer or head and neck cancer suggest that the widespread acquired resistance to immunotherapy drugs known as checkpoint inhibitors may be due to the elimination of certain genetic mutations needed to enable the immune system to recognize and attack malignant cells. The study, conducted by researchers on the cells of five of their patients treated at the Johns Hopkins Kimmel Cancer Center, is described online Dec. 28 in Cancer Discovery.”

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If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.


Super ASK Patient: Lance Williams Navigates Treatment for Head and Neck Cancer

Update:  We are deeply saddened to report that Lance passed away on August 20, 2017. It is a privilege to continue to share his story and help keep his memory alive.

 

Lance Williams was diagnosed with head and neck cancer in 2012. Since then, he has undergone multiple lines of treatment, and he has used our ASK service to better understand his treatment options. We interviewed Lance about his treatment experience via email.

Can you tell us a bit about yourself?

I’m 67, married with two grown boys (19 and 20), a computer scientist. I’ve worked in computer graphics, animation, and visual effects since the field was just getting off the ground. My wife and I met at a computer graphics lab in New York. We’re now living in Los Angeles, California, where I’ve worked for Dreamworks and Disney. My most recent employment is in the research division of Nvidia, a firm that develops computer graphics and artificial intelligence hardware.

How was your cancer first diagnosed?

I was initially mistakenly diagnosed with gastroesophageal reflux disease (GERD). The correct diagnosis of squamous-cell carcinoma of the head and neck (in my case, at the base of the tongue) was determined after a biopsy in 2012.

What was your initial treatment approach? How did you decide on it?

My wife Amber and I barnstormed the country, soliciting treatment plans from a number of clinics. Beginning close to home at the University of Southern California (USC), we then visited the Mayo Clinic in Minnesota, where surgical resection was considered, MD Anderson in Texas, which advocated induction chemotherapy followed by radiation, and Memorial Sloan Kettering in New York, which suggested concurrent chemotherapy and image-guided radiation. Our interviews at the different clinics were supplemented by frequent reference to PubMed.

Surgery would have been an extensive, perhaps heroic undertaking. Ultimately we were persuaded by the most recent studies that induction was inferior to immediate chemoradiation. I’d worked previously with Dr. David Agus on the computer end of a cancer proteomics project, and he kindly recommended Dr. David Pfister at Memorial Sloan Kettering. I received concurrent image-guided radiation therapy at Memorial Sloan Kettering under the supervision of Dr. Nancy Lee.

Treatment was briefly interrupted by Hurricane Sandy, but Memorial Sloan Kettering was fortunately above the water line.

 After your initial treatment, what treatments did you do and how did you choose them?

Six months after we left Memorial Sloan Kettering with “no evidence of disease,” a hot mediastinal (chest) lymph node showed up in a PET scan. We returned to New York for surgery. The node was resected laparoscopically, and the pathology report indicated it was a recurrence of my original cancer, outside the field irradiated. The surgery was followed by “clean-up” radiation of the immediate region.

In 2015, additional hotspots were visible on a scan, and it was clear I had metastatic disease. We asked what the median survival was with the best available treatment. The answer: 18 months. “No one has demonstrated extended survival with any treatment,” my oncologist at Cedars-Sinai, Los Angeles, told me. That turned out to be not quite true. The oncologist who had treated me in New York, Dr. David Pfister, recommended a protocol termed EXTREME (ERBITUX in first-line Treatment of REcurrent or MEtastatic head and neck cancer), which had extended both average survival without progression, and survival, if only modestly. It’s a harsh treatment, combining two chemotherapy agents, cisplatin and 5-fluorouracil, and a targeted agent, cetuximab. I embarked on a course of EXTREME chemotherapy at Cedars-Sinai, treated by oncologist Dr. Solomon Hamburg.

What were your other treatment considerations?

When my cancer was first diagnosed, I asked the clinic to send some of the sample taken for biopsy to FoundationOne for sequencing. In the course of time, tumor sequencing can be expected to provide more and more useful information relevant to possible treatments. The Washington Post recently reported that a committee of experts and patient advocates recommended that the Joseph Biden cancer “moonshot” initiative help “ . . . to better tailor treatment by helping more patients get their tumors genetically profiled.”

The FoundationOne report identified a mutation called E542K in a gene called PIK3CA. This gene is part of the PI3K pathway, a cellular network that helps regulate a number of important processes, including cell growth, proliferation, differentiation, motility, and survival. Mutations that enhance the activity of PIK3CA, such as E542K, have been found in 8% to 11% of head and neck squamous cell carcinoma tumors, and 49% of these types of tumors have been found to have high expression of PIK3CA. According to FoundationOne, researchers are currently testing drugs that inhibit PI3K in solid tumors. In clinical trials, these drugs are being tested alone or in tandem with other therapies.

Because of this report, I sought to augment my treatment with over-the-counter agents purported to downregulate the PI3K / Akt / mTOR pathway. After some reading on the web, with repeated reliance on PubMed, I came up with a list of substances with purported activity in suppressing the PI3K pathway. This general review was particularly helpful: The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals. These three papers are also worth noting: JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade, The natural chemopreventive agent sulforaphane inhibits STAT5 activity, and Radiosensitization of head and neck cancer cells by the phytochemical agent sulforaphane.

Some of the substances mentioned in the general review work additively or synergistically with one another, but that can’t be guaranteed for all of the substances I considered. Most of the research that has investigated these substances was conducted in the laboratory, and the findings have not been translated to human cancers. The doses of these agents used in the lab usually far exceed the amounts that could be safely given to human beings. The biggest drawback to dietary supplements is that they are largely unregulated by the FDA. In some spot-checks of over-the-counter supplements, many were found not to contain the ingredients on the labels. The FDA has resisted assuming responsibility for “health food” products, and the supplement industry has vigorously resisted government regulation of safety or effectiveness, which are required for pharmaceuticals. Of course, counterfeit pharmaceuticals are not unknown, either. I subscribe to Consumer Lab‘s circulars, which post evaluations of a range of supplements, but many of the supplements I took have so far not been reviewed.

[A note from our chief scientist, Emma Shtivelman: The FDA has a useful list of 187 fake cancer “cures” known to be falsely advertised on the web, and Sloan Kettering has a very useful site that lists many herbal supplements and explains their true relevance to cancer treatment.]

“mTOR” is the mechanistic Target ORapamycin, and the drug rapamycin is immunosuppressive — it’s administered to prevent rejection of transplanted organs. It follows that effective blockade of PI3K / Akt / mTOR would act to suppress the immune system, and during my EXTREME treatment, I suffered viral, bacterial, and fungal infections (including paronychia, infection of the beds of my fingernails, something like miniature puffballs growing in my ears, and the florid pustules shown in the photograph below. Perhaps this attests to the effectiveness of my improvised regimen of phytochemicals, but the chemotherapy itself was immunosuppressive, so it’s a little hard to say.

What side effects did you have during your initial treatment and during EXTREME?

I developed a rash in the irradiated region during my initial treatment at Memorial Sloan Kettering in New York:

In this photo taken on February 23, 2015, you can see the effects of the EXTREME chemotherapy treatment. This regimen combines cisplatin, cetuximab, and fluorouracil. The Epidermal Growth Factor protein plays a role in maintaining the skin, as well as contributing to the growth of some tumors; cetuximab (Erbitux™) blocks its receptor, hence the skin side effects:

rash2

You eventually decided to enroll in a clinical trial. How did you choose one, and what was the outcome?

After three cycles of treatment with the EXTREME protocol, my cancer progressed. At this point, conventional treatment had been exhausted, and the only recourse was to pursue research medicine. We began consulting ClinicalTrials.gov in search of the most promising clinical trials for my disease.

With the assistance and guidance of Cancer Commons’ Chief Scientist, Dr. Emma Shtivelman, we finally settled on a clinical trial that took me to the National Institutes of Health (NIH) in Bethesda, Maryland, for treatment.  The trial was called T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers. It tested a treatment that involved “taking white blood cells [T cells] from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient.”

This illustration outlines the treatment in the trial. The part we didn’t properly appreciate when deciding on the treatment falls under step 3: lymphodepleting conditioning. That suppressed my immune system (and my red blood cells and platelets), and they went well below normal (I remain depleted to this day). My depressed platelet count made me ineligible for subsequent clinical trials, and my reduced CD4 and CD8 levels arguably reduced the effectiveness of immune checkpoint inhibitors. Credit: Caron A. Jacobson and Jerome Ritz

At the time we made this choice, immunotherapy had made great strides, and seemed to be the most promising course. But there were a number of approaches among which to choose. Great success was taking place using drugs called “immune checkpoint inhibitors.” The immune system walks a tightrope between successfully defending the body against pathogens (viral, bacterial, or fungal infection), and recklessly attacking the body’s own tissues (as it does in lupus erythematosusand rheumatoid arthritis). To forestall such autoimmune conditions, the body employs a number of “checkpoint” signals, which (figuratively) tell T cells that there’s nothing to see here, move along, and dampen immune response. Unfortunately, many cancers evolve to exploit these shields against immune response. In the case of my own cancer, it often expresses a signal called PD-L1, which elicits an agent, PD-1, which protects tissues against T cells. Drugs like Opdivo and Keytruda are immune checkpoint inhibitors that target PD-1, making the T cells once again sensitive to foreign antigens expressed by tumors. In the case of cancer arising from HPV infection, tumors may exhibit targets (like HPV-16 E6) that are foreign to the body; they are expressed nowhere in healthy human tissue.

We had two major considerations that weighed in favor of seeking the T cell immunotherapy in the trial, instead of immunotherapy drugs like Opdivo and Keytruda. First, T cell immunotherapy was an elaborate and expensive protocol. Having it administered in a clinical trial was, at the time, the only way we might have access to it. If it subsequently became available, it would probably be an exotic procedure which medical insurance might easily refuse to cover. Second, if the “chimeric” (lab-altered) T cells infused in this treatment failed to destroy my cancer, they might (if they survived) succeed in doing so with the subsequent administration of a checkpoint inhibitor drug.

This argument seems persuasive, but we’d neglected to consider one important thing. In the process of treatment, in order to maximize the percentage of transformed T cells in my body, and reduce other white blood cells called macrophages that might compete with them for tumor-fighting cytokines, my current T cells would be systematically depleted with rather harsh chemotherapy.

The EXTREME chemo undertaken at Cedars-Sinai was arguably harsh, but it was not actually as debilitating as the T cell ablation chemotherapy applied in this trial, which also caused me to lose my hair, at least temporarily. Afterward, the agent used to induce the T cells infused into my bloodstream to proliferate, aldesleukin (IL-2, GM-CSF, Proleukin™), induced a sort of delirium, with lurid dreams and hallucinations.

The result was dramatic. My tumors shrank by 40%. I returned to the NIH in Bethesda at intervals after the procedure to monitor my disease. The third visit showed my cancer had progressed, which was an endpoint for the clinical trial. For me, it was over, and I was not asked to return.

The NIH trial team near the conclusion of my treatment. Dr. Steven Rosenberg is prominent on left; he heads the National Cancer Institute’s Tumor Immunology Section, and is a pioneer in immunotherapy. The Principal Investigator on this trial, Dr. Christian Hinrichs, is in the doorway. He had a cold at the time, and I was (and remain) immunosuppressed.

On April 20, 2016, the scientific journal Nature reported:

US agency suspends clinical trials after contamination risk discovered.

Two NIH facilities that manufacture products for use in patients have been shut down because of safety violations.

Oncologist Steven Rosenberg’s lab at the National Cancer Institute (NCI) in Bethesda, Maryland, is one of the two facilities affected. Rosenberg is developing cancer therapies using immune cells called T lymphocytes, which he engineers to attack a specific patient’s cancer. After discovering problems with Rosenberg’s cell-manufacturing lab, the NCI suspended 13 trials that used materials from the facility…

The safety violations came to light during a sweeping NIH-wide review that began last year. It was prompted by the discovery of widespread contamination by the US Food and Drug Administration (FDA) in a facility at the NIH Clinical Center in Bethesda that manufactures customized drugs for use in clinical trials. A whistleblower’s tips led FDA investigators to fungal contamination in materials intended for injection into patients, lab workers with uncovered hair, and insects in the light fixtures.

…Discouraging news.

You are now receiving Opdivo and radiation. How did you settle on these, and how is it going so far?

So far, it seems to be going well. I tolerated Opdivo well, with intermittent diarrhea and fatigue as the primary side effects. My oncologist at the Angeles Clinic in Los Angeles, Dr. Omid Hamid, just switched my treatment to pembrolizumab (Keytruda), which is also an immune checkpoint inhibitor, targeting PD-1. The two drugs are largely interchangeable, but infusions of Keytruda are given once every three weeks versus every two weeks for Opdivo, which is easier for me to schedule. Image-based radiation therapy will be used to target the regions where my cancer has progressed.

How did you hear about Cancer Commons, and why did you reach out?

Cancer Commons was originally suggested to me by Prof. Al Barr, an old friend at California Institute of Technology. I visited the Cancer Commons web site and ended up corresponding with its founder, Marty Tenenbaum, and with researcher Emma Shtivelman. Emma has been a great help, interpreting cancer research trials and suggesting and helping us choose the most promising clinical trials.

What advice would you give to someone else who has just been diagnosed?

I would tell them that there are many reasons to be hopeful, and that recent research, particularly in immunotherapy, has produced more effective treatments than ever before. I would urge them to investigate clinical trials relevant to their disease. Many of these are testing extremely promising agents and protocols. Clinical trials advance understanding for everyone, but they are largely unsubscribed. They enroll only a small percentage of eligible patients.

Is there anything else you would like to tell us?

For cancer immunotherapy patients, a couple of adjuvants in particular are worth considering: tadalafil (Cialis), which downregulates myeloid-derived suppressor cells (which act to suppress immune response), and bifidobacteria probiotics seem to be safe approaches to potentially augment treatment. I use Procter & Gamble’s Align (bifidobacterium infantis) and 4x Probiotic (Leader®bifidobacterium infantis, bifidobacterium lactis, bifidobacterium longum, and bifidobacterium bifidum).

PubMed is an invaluable resource, with reference to a great many technical papers and reviews of agents and treatments; ClinicalTrials.gov references current clinical trials, but, in my view, it is not well-maintained, and many of its entries are out-of-date. Both are offered by the NIH.

***

Super Patients are cancer survivors who learned to be more engaged in their own care. Cancer Commons believes every patient can be a Super Patient or benefit from a Super Caregiver. We hope these stories will provide inspiration and hope for your or your loved one’s own treatment journey.


AstraZeneca Widens Cancer Immunotherapy Net with Advaxis Trial

The gist: Cancer treatments called immunotherapies, which boost a patient’s own immune system to fight cancer, are currently a very active focus of research for drug companies. Two drug companies have now decided to collaborate and combine their two immunotherapy drugs to see how well they work for people with HPV-associated cervical cancer or head and neck cancer. The two companies will jointly run a clinical trial with volunteer patients to test the combination treatment, in the hope that the combo will work better than either drug alone. The drugs being combined are MEDI4736 and ADXS-HPV.

“AstraZeneca is casting its net wider in the hot cancer immunotherapy field through a clinical trial collaboration with U.S. biotech firm Advaxis that will test drugs from both companies in combination.

“Britain-based AstraZeneca – the target of an unsuccessful $118 billion takeover bid by Pfizer earlier this year – is banking on widespread use of its immunotherapy drugs, which boost the body’s immune system, to fight a range of tumours.

“Under the deal with Advaxis, its so-called anti-PD-L1 drug MEDI4736 will be evaluated in a Phase I/II clinical study together with the U.S. company’s cancer vaccine ADXS-HPV in patients with human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer.”


Advances in Immunotherapy Brighten Prospects for People with Cancer

The enthusiasm for anticancer immunotherapies continues to build, with two treatments already approved by the U.S. Food and Drug Administration (FDA) and clinical trials underway for a variety of promising new candidates. The latest approaches include targeting a protein called PD-L1, which shields tumor cells from immune system attacks. In a phase I clinical trial of a PD-L1 blocker made by MedImmune, early results suggest that this treatment shrinks melanomas as well as kidney, lung, and colon tumors. Next, the researchers hope to open this trial to people with head and neck cancers as well. Another approach entails adding the gene for an immune system booster (interferon beta) to a therapeutic virus (vesicular stomatitis virus) that kills cancer cells, but not normal ones. This treatment is being tested on liver cancer in a phase I trial and early results are encouraging.


Advances in Immunotherapy Brighten Prospects for People with Cancer

The enthusiasm for anticancer immunotherapies continues to build, with two treatments already approved by the U.S. Food and Drug Administration (FDA) and clinical trials underway for a variety of promising new candidates. The latest approaches include targeting a protein called PD-L1, which shields tumor cells from immune system attacks. In a phase I clinical trial of a PD-L1 blocker made by MedImmune, early results suggest that this treatment shrinks melanomas as well as kidney, lung, and colon tumors. Next, the researchers hope to open this trial to people with head and neck cancers as well. Another approach entails adding the gene for an immune system booster (interferon beta) to a therapeutic virus (vesicular stomatitis virus) that kills cancer cells, but not normal ones. This treatment is being tested on liver cancer in a phase I trial and early results are encouraging.