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Immunotherapy: A prematurely-abandoned treatment option


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Larry Weisenthal, M.D., PhD.

Medical and Lab Director

Weisenthal Cancer Group; Huntington Beach, CA

Clinical trials are warranted to test macrophage-activating biologic response modifiers administered following chemotherapy of ovarian and breast cancers. This is based on (1) striking in vitro findings in fresh human tumor cell culture assays, (2) supportive data from pilot clinical trials, and (3) a sound mechanistic rationale. I would advocate sequential administration of (1) assay-directed chemotherapy, (2) "non-specific" immunotherapy (e.g. antigens derived from bacteria), and (3) more "specific" cytokine therapy (e.g. interferon gamma).

In 1991, my colleagues and I published a study (1,2) in the Journal of the National Cancer Institute which I hoped would receive scrutiny and follow-up. This was a tumor immunology study which grew out of a contract research project. Continuing this research was at the time not an option, as my priorities were to establish a clinical laboratory to provide cell culture drug resistance testing.

In the 1991 study, we presented the concept of "in situ vaccination," based upon our studies of biologic response modifiers in the DISC assay. We found that there was a striking association between the activity of biologic response modifiers which activate macrophages and the prior treatment status of patients with breast and ovarian cancers. Color photomicrographs illustrating method.

http://weisenthal.org/jnci83_38_91f1.jpg

The following agents were dramatically more active in fresh tumor specimens from previously-treated breast and ovarian cancer patients than against specimens from untreated patients:

1. ImuVert (a potent macrophage activator derived from Serratia marcescens)

2. Interferon gamma, and

3. Tumor necrosis factor

This greater activity in specimens from treated versus non-treated patients was not observed in adenocarcinomas known to be relatively resistant to chemotherapy (colon cancer, non-small cell lung cancer, etc.). Graphs showing representative results.

http://weisenthal.org/jnci83_39_91.jpg

This differential activity was also not observed in agents which are not potent macrophage activators (interleukin-2 and interferon alpha).

Based on these findings (and supported by anecdotal studies in the clinical trials literature), we proposed that effective chemotherapy produces massive release and processing of tumor antigens, which leads to a state in which the human immune system is primed (via "in situ vaccination") to respond to exogenous macrophage-activation signals with potent, specific antitumor effects.

In the above-quoted study (1), I reviewed a diverse clinical trials literature which supported this concept. More recently published was a randomized trial in previously untreated ovarian cancer (3) , in which cisplatin/cyclophosphamide was compared to the same chemotherapy plus interferon gamma, administered subcutaneously three times a week, every other week, for the duration of chemotherapy (6 plannned treatment cycles). The study was prematurely closed because chemotherapy standard treatment had changed from platinum/cyclophosphamide to platinum/Taxol, but, even with the low power of the small numbers of patients accrued to show a difference, there was a significant advantage to combined treatment in progression-free survival and a soft trend for improved overall survival. The authors quoted our earlier work1 in providing a mechanism for their positive results and called for follow-up clinical trials. Progression-free survival curves.

http://weisenthal.org/bjc82_1138_00.jpg

As noted above, my preferred trial design would be (1) first complete (preferably assay-directed) chemotherapy, then (2) administer non-specific immunotherapy to responders, then (3) provide more specific cytokine therapy, e.g. interferon gamma.

Literature Citation:

1. Weisenthal LM, Dill PL, Pearson FC (1991) Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst 83: 37-42

2. Weisenthal LM (1991) Effect of prior chemotherapy on biologic response modifier activity. J Natl Cancer Inst 83: 790-791

3. Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, et al. (2000) Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase 3 trial. Br J Cancer 82:1138-1144, 2000.

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Preclinical, laboratory studies suggest immunotherapy could potentially work like a vaccine against metastatic cancers.

Results from the recent study show the therapy could treat metastatic cancers and be used in combination with current cancer therapies while helping to prevent the development of new metastatic tumors and train specialized immune system cells to guard against cancer relapse.

The study detailed the effects of a molecule engineered by lead author Xiang-Yang Wang, Ph.D., of Virginia Commonwealth University Massey Cancer Center, on animal and cell models of melanoma, prostate and colon tumors. The Flagrp-170 molecule consists of two distinct proteins, glucose-regulated protein 170 (Grp170), known as a "molecular chaperone," and a "danger signal" derived from flagellin, a protein commonly found in bacteria. The researchers used modified viruses, or adenoviruses, that can no longer replicate to transport Flagrp-170 directly to the tumor site to achieve localized vaccination. The novel therapy caused a profound immune response that significantly prolonged survival in animal models.

Grp170 is currently being explored for its potential as a "cancer vaccine" because it has been shown to help the immune system recognize cancer antigens. Antigens are molecules from foreign objects such as bacteria, viruses or cancer that, when detected, provoke an immune response aimed at attacking them. However, because cancer cells can alter the microenvironment surrounding a tumor, they are able to suppress immune responses and continue replicating without being attacked by the body's natural defenses.

The chimeric chaperone Flagrp-170, created by strategically fusing a fragment of flagellin to Grp170, not only enhances antigen presentation, it also stimulates additional immune signals essential for functional activation of specialized immune cells, including dendritic cells, CD8+ T lymphocytes and natural killer (NK) cells. Dendritic cells act as messengers between the innate and adaptive immune systems.

Once activated in response to a stimulus such as Flagrp-170, dendritic cells migrate to lymph nodes where they interact with other immune cells such as T lymphocytes to shape the body's immune response. CD8+ T lymphocytes and NK cells are known to respond to tumor formation and kill cancer cells by triggering apoptosis, a form of cell suicide.

"Overcoming cancer's ability to suppress the body's natural immune responses and restore or develop immunity for tumor eradication is the goal of cancer immunotherapy," says Wang. "More experiments are needed, but we are hoping Flagrp-170 may one day be used in formulating more effective therapeutic cancer vaccines."

Moving forward, the researchers are working to better understand the molecular mechanisms responsible for Flagrp-170's therapeutic effects.

Additional studies are underway to more efficiently target and deliver Flagrp-170 to tumor sites in order to provoke a more robust and durable immune response.

Source: Cancer Research

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Tumor cell evolution enables cancer cells to evade destruction by the immune system. Cells that can be destroyed are destroyed. What is left is resistant to immune destruction. The mechanisms of escape are extremely diverse.

Tumor cells can lose the antigens (a molecule that the immune system reacts against and attacks) that trigger an immune response. In addition, tumor cells can inhibit the immune response, or develop resistance to the killing mechanisms involved.

For a tumor to grow and cause disease in the first place, it must evade destruction bv the immune system. The immune response is therefore a major selective pressure that directs the flow of tumor cell evolution.

This is one reason that immunotherapy has had so little success in the cure or chronic control of cancer in patients.

Tumor cells evolve that not only escape destruction by immune attack, but also that subvert normal immune cells to enhance tumor growth. Tumors recruit normal white blood cells to help in the process of tissue invasion.

Tumors also can release soluble factors that stimulate normal cells to produce enzymes that digest connective tissue and facilitate invasiveness. It's like renting bulldozers to clear space for new apartment houses.

The limitations of narrowly targeted therapy are also seen with cancer vaccines and immunotherapy. The earliest approaches at targeting tumor-specific molecules involved attempts to turn the immune system against proteins that are unique to cancer cells.

Certain types of lymphoma have a unique, patient-specific antibody on the surface of the lymphoma cells. The lymphoma cells make this antibody, which is absent from normal cells. Patients have been treated with antibodies targeted to the particular antibody on their lymphoma cells.

This antibody-against-an-antibody was prepared specially for each patient. In a study of 45 patients, eight responded. Only six patients had long-term control of their disease. The problem is that lymphoma cells can and do evolve without the surface antibody marker (Blood. 1998 Aug 15;92(4):1184-90).

Dr. Steven A. Rosenberg, Chief of Surgery at the National Cancer Institute (NCI) and a leading cancer immunologist, published a review of clinical trials on cancer vaccines. His analysis revealed that the overall response rate among 765 patients in a large number of different trials was only 3% (Nat Med. 2004 Sep;10(9):909-15).

Reference: "Cure: Scientific, Social and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. 2005

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Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer

At the 2012 ASCO trade show, there were separate presentations of the immune checkpoint inhibitor in renal cell carcinoma (RCC), melanoma and lung cancer. The data sets were amplified by simultaneous New England Journal publications. Approximately a quarter of patients with RCC were shown to have objective responses, ans as with high-dose IL-2, a small subet remain progression free a number of years out. To some clinicians, treatment is generally well tolerated, particularly in contrast to the checkpoint inhibitor of the CTLA-4 pathway (ipilimumab), which is currently approved in melanoma. There is a soon-to-be launched Phase III trial comparing this immune agent to everolimus for patients with disease progression on VEGF/TKIs.

N Engl J Med. 2012 Jun 28;366(26):2443-54. Epub 2012 Jun 2.

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M.

Department of Surgery, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. [email protected]

Abstract

BACKGROUND:

Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.

METHODS:

We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.

RESULTS:

A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006).

CONCLUSIONS:

Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).

Comment in

The future of cancer treatment: will it include immunotherapy? [Cancer Cell. 2012]

Tumor immunotherapy directed at PD-1. [N Engl J Med. 2012]

From ASCO-immunotherapy: programming cancer cell death. [Nat Rev Clin Oncol. 2012]

PMID: 22658127

http://www.ncbi.nlm.nih.gov/pubmed/22658127

Immunological Research: A multi-faceted approach to curing disease

http://cancerfocus.org/forum/showthread.php?t=3901

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Jessica Yarber, M.D.

An experimental cancer drug successfully shrank tumors in patients with different kinds of cancer, including typically hard-to-treat lung cancers, according to a new study. Oncologists said the research was encouraging, but more study was needed to know whether the drug would prolong life for cancer patients.

The study, led by Dr. Suzanne Topalian, was presented at a meeting of the American Society of Clinical Oncology, and published in the New England Journal of Medicine.

In a small, early phase study, researchers used a drug targeting a portion of the body's immune system, a pathway called PD-1, which usually works to stop the body from fighting cancerous tumors. By shutting down the pathway, the drug stokes the body's immune system to fight tumor cells.

Researchers gave the drug to nearly 240 patients with advanced melanoma, colorectal, prostate, kidney and lung cancers. All the patients had tried up to five other treatments, which failed. After up to two years on the drug, tumors shrank in 26 of 94 patients with melanoma, nine of 33 patients with kidney cancer and 14 of 76 patients with lung cancer.

The drug was not without side effects. About 14 percent of patients in the trial reported conditions such as skin rashes, diarrhea or breathing problems.

Cancer specialists said the fact that the drug caused tumors to shrink, rather than simply to stop growing, is an important measure of success.

"Traditionally in cancer medicine, a tumor that shrinks is an indication that you're killing the cancer," said Dr. Jay Brooks, chairman of hematology and oncology at Ochsner Health System in Baton Rouge, La.

To see that kind of success against several different kinds of cancer, particularly against melanoma, kidney and lung cancers, which are notoriously unresponsive to many of the usual treatments doctors use to thwart them, was also unusual.

"To see this kind of response in cancers that are so difficult to treat is very encouraging," said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society.

The study did not show whether patients lived longer after taking the drug, but experts said early phases of drug trials typically aren't designed to determine improvements in survival. As scientists study the drug in larger numbers of patients for longer periods of time, the drug's success in prolonging life for cancer patients will become clearer.

Lichtenfeld also noted that early trials of drugs are intended to show whether a drug is safe, and don't usually find impressive numbers of patients who respond to the drug. To see those numbers emerging early in drug trials is encouraging, he said.

The difference in the drug's early success may lie in the approach it takes in delivering targeted cancer therapy. Cancer researchers have been chasing more targeted ways to deliver cancer treatments for decades now, in search of a method more refined than the "slash, burn and poison" approaches available with traditional chemotherapy. Usually, targeted therapies home in on a particular part of the cancer itself – a particular kind of cell or a process vital to a tumor's survival.

The current drug is a different because it targets the body's own immune system, training it to recognize tumor cells as foreign, malicious agents.

"In spite of everything we've done so far with cancer drugs, chemotherapy and the rest, what could be more powerful than having the body's own immune system attack the cancer?" said Dr. Roy Herbst, chief of medical oncology at Yale Cancer Center.

Still, doctors remain cautiously optimistic about the drug's early promise.

"In all new studies, there's usually a lot of optimism and hope, but this should all be tempered with a dose of realism," Brooks said. "What's initially reported may not necessarily pan out with time."

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An experimental drug that’s designed to unleash the body’s immune-system defenses against cancer sets the stage for an industry wide race to produce similar treatments.

The drug shrank tumors in people with advanced lung, kidney and skin cancer in 18 - 28 percent of patients, depending on the illness, who had failed on other therapies, according to data from a 296-patient trial reported at the American Society of Clinical Oncology (ASCO) meeting.

The findings hint that therapies that prompt killer T-cells to eliminate invaders, may work against many tumors, said James Allison, an immunologist at Memorial Sloan-Kettering Cancer Center in New York.

“There is no reason to think that all cancers might not be susceptible to immune therapy,” Allison told Bloomberg News, noting that the human immune system can wipe out whole organs when it rejects a transplant.

Drugmakers and scientists have been trying to find ways to boost the immune system against cancer for decades, with little successes until recently.

In 2010, Provenge, a prostate cancer treatment, was approved in the U.S. as the first therapy designed to train the body’s immune system to attack tumor cells as if they were a virus. Last year, the immune boosting antibody Yervoy was approved for advanced melanoma.

In the 1990s, Allison did pioneering work that led to Yervoy. Yervoy was the first drug proven to extend the survival of advanced melanoma patients. The therapy blocks a molecular off-switch on the immune cells that keeps them from attacking cancer. It has been shown in studies to shrink melanoma in 10 percent to 15 percent of patients.

The newest drug, BMS-936558, is an antibody that blocks a different immune system off-switch, called PD-1. Many types of tumors act to keep the off-switch in place to protect themselves from the immune system.

Results from a company-sponsored trial reported at the cancer meeting showed The anti-PD-1 drug shrank tumors in 18 percent of lung cancer patients, 27 percent of kidney cancer patients and 28 percent of melanoma patients.

A promising aspect of new immune-boosting therapies is that they may work for long periods of time, said Suzanne Topalian, a professor of surgery and oncology at Johns Hopkins University School of Medicine in Baltimore and a lead author on the study.

According to the results, 20 patients on the PD-1 drug had tumor responses that have lasted a year or more. This stands in contrast to existing drugs that hit mutated genes on cancer cells. These often stop working in a matter of months as the tumors become resistant.

Some patients who responded to BMS-936558 have now gone off therapy without their tumors regrowing, Topalian said. The immune system “has a memory component that continues to hold to the tumor in check” even after therapy is stopped.

A downside of boosting the immune system against cancer is that it may also attack normal tissue. Three patients in the trial died from lung inflammation linked to the drug, according to the results.

There haven’t been any deaths since they started a program to aggressively treat patients who showed signs of the lung inflammation.

In addition to lung, kidney and melanoma patients, the drug trial also included people with advanced colon cancer and prostate cancer. None of those patients experienced major tumor shrinkage, for reasons that aren’t clear.

Tumor-Cell Death, Autophagy, and Immunity

http://cancerfocus.org/forum/showthread.php?t=3651

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Safety and activity of anti-PD-L1 antibody in patients with advanced cancer

N Engl J Med. 2012 Jun 28;366(26):2455-65. Epub 2012 Jun 2.

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM.

Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.

Abstract

BACKGROUND:

Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models.

METHODS:

In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression.

RESULTS:

As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up.

CONCLUSIONS:

Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

Comment in

The future of cancer treatment: will it include immunotherapy? [Cancer Cell. 2012]

Tumor immunotherapy directed at PD-1. [N Engl J Med. 2012]

From ASCO-immunotherapy: programming cancer cell death. [Nat Rev Clin Oncol. 2012]

PMID: 22658128

http://www.ncbi.nlm.nih.gov/pubmed/22658128

Up and coming immunotherapy for lung cancer?

New research at Washington University School of Medicine in St. Louis suggests a key immune cell may play a role in lung cancer susceptibility. Working in mice, they found evidence that the genetic diversity in natural killer cells, which typically seek out and destroy tumor cells, contributes to whether or not the animals develop lung cancer. The research is published in the the journal Cancer Research.

https://news.wustl.edu/news/Pages/24264.aspx

Targeting Cancer With New Strategies

http://cancerfocus.org/forum/showthread.php?t=847

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