Posts Tagged ‘gastrointestinal carcinomas’

Checkpoint inhibitors for gastrointestinal cancers

Larry H. Bernstein, MD, FCAP, Curator


Updated 5/03/2019

Modern Immunotherapy for the Treatment of Advanced Gastrointestinal Cancers –

Oncology Journal, Gastrointestinal Cancer    January 15, 2016



Since the first immune checkpoint–blocking monoclonal antibody was approved in the United States in 2011 for the treatment of advanced cancer, the rate of progress in the field of cancer immunotherapy has only accelerated. This mode of cancer treatment has yielded durable complete responses in a subset of patients with metastatic cancer for whom no other treatment was effective. It is a class of therapy that is not inherently cancer type–specific, and investigators are only beginning to understand why some cancers, such as melanoma, are more sensitive to immunotherapy than others. Although immunotherapy is not yet approved for the treatment of gastrointestinal cancers, it is already clear that many gastrointestinal cancers can be sensitive to it. We will review recent clinical trial results demonstrating this, and offer our perspective on the role that immunotherapy might play in the treatment of advanced gastrointestinal malignancies in the years ahead.

Introduction Immunotherapy can be defined as a therapeutic intervention that is focused on the immune system, as opposed to the cancer itself. Thus, it becomes the patient’s own immune response, rather than an exogenous drug, that acts directly against the disease. This approach to the treatment of cancer is viewed by many as a modern paradigm shift in oncology, in part because of recent successes of immune checkpoint blockade in diverse cancers.[1-3] It is important to keep in mind, however, that attempts to recruit the immune system in the effort against cancer are not new, and there is much to learn from early experiences in the field.

Immunotherapy has long been part of the standard treatment for early-stage cancers. For example, the intravesical Bacillus Calmette-Guérin vaccine and topical imiquimod are used to treat non–muscle-invasive bladder cancer and superficial basal cell carcinoma, respectively. Both of these agents are immunostimulants that function by activating immune cells in an antigen-nonspecific manner.[4,5] Their efficacy suggests that directing the immune response to a specific target is unnecessary in some cases, presaging disappointing efforts in therapeutic cancer vaccination designed to direct the immune system to targets associated with malignant cells.[6,7]

The experience with systemic immunotherapy for cancer in prior decades has been more controversial. High-dose interleukin (IL)-2 treatment for renal cell carcinoma and melanoma has led to extremely durable responses for a minority of patients, but has also led to excessive toxicity for others.[8] Without evidence of improved overall survival (OS) in a large randomized clinical trial, the precise setting for this therapy in patient care has been disputed. Nevertheless, IL-2 allowed the oncology community to glimpse both the potential efficacy and the potential harms of using the immune system to treat metastatic cancer.



Immune Checkpoint Blockade

Immune checkpoint blockade represents a class of anticancer agents that function by blocking inhibitory immune cell receptors. Among the most important members of this category are monoclonal antibodies (mAbs) that block cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) or its ligand PD-L1. After an antigen-presenting cell (APC) captures a tumor-associated antigen, it presents a portion of the antigen as a peptide to naive T cells in the context of a so-called immunologic synapse. Both stimulatory and inhibitory signaling between the T cell and the APC occur at this synapse. One inhibitory T-cell receptor that functions in this context is CTLA-4; therapeutically blocking CTLA-4 strengthens the immunogenic signal that the APC transmits to the T cell. Once the T cell is activated by the APC, it can then encounter a malignant cell presenting a cognate peptide and mediate its lysis. It is at this phase that the T cell encounters another set of inhibitory signals, including PD-L1 and PD-L2, which are both recognized by PD-1 on T cells. Anti–PD-1 mAbs block this interaction and thus enhance the ability of the activated T cell to lyse its target cell.

Immune checkpoint blockade as a means of treating cancer rose to prominence in 2010 when the anti–CTLA-4 mAb ipilimumab was found to improve median OS for patients with metastatic melanoma from 6.4 to 10 months.[7] This result was important for a number of reasons. First, ipilimumab was the first therapy to improve OS in this patient population in a phase III clinical trial. Second, since an independent study arm incorporated a therapeutic vaccine, it showed that such antigen-directed therapy did not add benefit in this context. Finally, it demonstrated that anti–CTLA-4 therapy can result in durable remissions.[9]

Following the unprecedented activity of CTLA-4 blockade, PD-1 blockade quickly rose to prominence. In fact, anti–PD-1 axis (ie, anti–PD-1 or anti–PD-L1) therapy showed response rates of over 40% in some melanoma studies,[1,10] and it has shown activity in a host of other malignancies, including non–small-cell lung cancer (NSCLC; response rate of 20%),[11,12] bladder cancer (response rate of over 40% in select patients),[3] and gastrointestinal malignancies, as discussed below.

The marked, but non-uniform, responses to checkpoint blockade triggered an international effort to identify biomarkers of response. PD-L1 expression in the tumor, whether on malignant cells or tumor-associated cells, was found to correlate with response to PD-1 axis blockade across a range of malignancies.[3,13,14] It should be noted, however, that a subset of tumors found to be PD-L1–negative did benefit from anti–PD-1 axis therapy, highlighting the fact that PD-L1 should not necessarily be used as a binary biomarker to predict response to therapy.

Although baseline PD-L1 expression correlates with response to PD-1 axis blockade, there is now evidence that genomic alterations may predict for response to checkpoint blockade more broadly. Whole-exome sequencing has demonstrated that mutation burden correlates with response to CTLA-4 blockade in melanoma,[15] and similar work revealed that mutation burden also correlates with response to PD-1 blockade in NSCLC.[16] It is not yet clear, however, that specific mutated sequences (so-called neoepitopes) reliably predict for response to any form of immunotherapy.[17] Such a finding, if prospectively validated, would enable clinicians to administer immunotherapy in much the same way that modern targeted therapies are used—based on the presence of discreet and predefined genetic lesions.

In addition, tumors that were responsive to checkpoint blockade were found to be more inflamed at baseline. For example, tumors rich in infiltrating T cells, and T helper 1 (Th1)-associated cytokines, were found to be particularly responsive.[18,19]

These findings do not only further our understanding of why immunotherapy is effective for some patients, but they also impact how immunotherapy will be used in the future. Therefore, they are of major significance as the field of immunotherapy begins to expand into gastrointestinal malignancies.


Pancreatic Cancer

Despite its historic intransigence, there are multiple lines of evidence indicating that pancreatic cancer can be responsive to immunotherapy. Pancreatic tumors have been found to exclude T cells at baseline in a manner that can be reversed.[20] Combination regimens designed to stimulate T cells with PD-L1 blockade and overcome T-cell exclusion via inhibition of the chemokine C-X-C ligand 12 (CXCL12) mediated tumor regression in an autochthonous animal model of pancreatic ductal adenocarcinoma.[21]

Based on clinical data, considering the paucity of responses to date, it is unlikely that anti–CTLA-4 therapy alone will have a role in the care of pancreatic cancer patients in the future. Nevertheless, there is instructive anecdotal evidence that even single-agent ipilimumab has activity among patients with pancreatic cancer. ….


Gastric Cancer

As with pancreatic cancer, responses to anti–CTLA-4 monotherapy in gastric carcinoma are rare and can be quite delayed. For example, in a phase II study of the anti–CTLA-4 mAb tremelimumab, 1 of 18 gastric cancer patients achieved a PR after 25 months on treatment.[30]

Consistent with other cancers, responses to PD-1 axis blockade in gastric cancer appear to be more frequent than responses to CTLA-4 blockade. Such results were anticipated by preclinical data showing that PD-L1 expression on gastric carcinoma cells, but not healthy gastric tissue or gastric adenomas, could induce T-cell apoptosis in a manner that was reversible with PD-L1–blocking mAbs.[31]

The anti–PD-1 mAb pembrolizumab is currently being tested in an ongoing phase I study of patients with adenocarcinoma of the stomach or gastroesophageal junction.[32] Preliminary results were presented at the European Society for Medical Oncology 2014 Congress. ….


Colorectal Cancer

There is extensive circumstantial data suggesting that colorectal cancer can respond to immune modulation. For example, colorectal cancer is generally associated with a relatively high mutation burden similar to other immune-responsive cancers, such as gastric and head and neck cancers.[33] In addition, there are reports associating immune signatures (eg, increased lymphocytes, especially cytotoxic and Th1 T cells, within the tumor or at the invasive margin) with improved prognosis.[34-36]

It is now apparent that two distinct immunologic subtypes of colorectal cancer exist, according to their mismatch repair (MMR) status. MMR deficiency occurs in approximately 4% of patients with metastatic colorectal cancer.[37] Tumors with MMR deficiency are rich in mutations that may be recognized as neoepitopes when presented to the adaptive immune system.[38,39] As would therefore be expected, MMR-deficient colorectal cancers are enriched for tumor-infiltrating lymphocytes.[40] This immunologic subtype of colorectal cancer represents an inherently sensitive population for T-cell stimulatory therapy. In a recently published phase II study of pembrolizumab,[41] 4 of 10 MMR-deficient patients had an immune-related objective response[23] vs 0 of 18 MMR-proficient patients. In an update presented at the 2015 American Society of Clinical Oncology Annual Meeting, which reported on 13 MMR-deficient and 25 MMR-proficient patients,[42] objective response rates were 62% and 0%, respectively. It is against this background that patients with MMR-deficient colorectal cancer will be evaluated for their response to pembrolizumab in phase II (Clinicaltrials.gov identifier: NCT02460198) and phase III (Clinicaltrials.gov identifier: NCT02563002) clinical trials; as well as for their response to durvalumab in an ongoing phase II study (Clinicaltrials.gov identifier: NCT02227667) we are currently conducting.


The Future of Immunotherapy in Gastrointestinal Cancers 

We are optimistic that immunotherapy will become standard of care in at least a subset of gastrointestinal malignancies. In the near term, we anticipate that PD-1 axis blockade will be incorporated into the care of patients with gastroesophageal cancer and MMR-deficient colorectal cancer, and perhaps others, as it has been for patients with NSCLC and melanoma.

CTLA-4 and PD-1 are only two receptors among over a dozen known inhibitory and stimulatory T-cell receptors that can be targeted to augment antitumor T-cell activity.[45] There are thus innumerable combination regimens that can be designed to boost the already notable activity of checkpoint blockade. Furthermore, receptors on other immune cell populations can be activated or blocked to synergize with T-cell stimulatory therapy.[46] For example, current clinical trials are coupling the blockade of an inhibitory killer-cell immunoglobulin-like receptor on natural killer (NK) cells with anti–CTLA-4 (Clinicaltrials.gov identifier: NCT01750580) and anti–PD-1 (Clinicaltrials.gov identifier: NCT01714739) mAbs.

Given that tumor antigen–targeting mAbs (eg, cetuximab, trastuzumab) are approved or in clinical development for several types of gastrointestinal cancers,[47-49] there is interest in enhancing their efficacy through stimulation of immune cells. NK cells represent an attractive target for such a strategy, as they can mediate antibody-dependent cell-mediated cytotoxicity of malignant cells bound by tumor-targeting mAbs. In one such study that includes colorectal cancer patients, cetuximab is being combined with the anti-CD137 agonist mAb urelumab, which is designed to stimulate NK cells, in addition to T cells (Clinicaltrials.gov identifier: NCT02110082).  …..

Although adoptive T-cell therapy is not yet ready for widespread clinical application, it has immense potential significance. Tran et al have effectively treated a patient with metastatic cholangiocarcinoma using CD4 T cells selected to recognize the product of a mutation specific to the patient’s tumor.[54] This type of adoptive transfer of selected, but unmodified, T cells has the notable limitation of being restricted to cancer-specific epitopes presented within patient-specific major histocompatibility complex (MHC) molecules. ….

The need for ex vivo manipulation to direct T cells to malignant cells in an MHC-independent manner can be circumvented using so-called bispecific T-cell engager (BiTE) technology. With this approach a therapeutic protein is constructed using mAb fragments specific to CD3 (present on the surface of T cells) and a molecule on the surface of the malignant cell. As with CAR technology, BiTEs have been studied primarily for the treatment of hematologic malignancies.[57] However, BiTEs that recognize the colorectal cancer–associated carcinoembryonic antigen have been developed,[58] and they will soon undergo clinical testing.


Most modern cancer immunotherapy is not inherently disease-specific. Furthermore, such treatments offer patients a chance at durable remissions, something not typically associated with cytotoxic chemotherapy or so-called targeted therapies. For these two reasons it is clear that, despite the remarkable successes to date, we are only at the start of an era in which the patient’s own immune system—with its unique combination of potency, specificity, and memory—begins to take the place of therapies that are designed to be directly toxic to malignant cells.

– See more at: http://www.cancernetwork.com/oncology-journal/modern-immunotherapy-treatment-advanced-gastrointestinal-cancers/page/0/2?GUID=08B7ACA4-07B7-4253-8ACC-0C9AAFF0371A&XGUID=&rememberme=1&ts=11022016#sthash.EnRTDdFt.dpuf

-see also

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN


Updated 5/02/2019

Lack of microsatellite instability in colon cancer dooms a Combination MEK/PD-L1 Inhibitor Trial

IMblaze370 a ‘great disappointment’ following promise in preclinical models

by Ian Ingram, Deputy Managing Editor, MedPage Today April 24, 2019


An immunotherapy and targeted therapy combination failed to improve survival over standard third-line therapy for patients with chemorefractory metastatic colorectal cancer (CRC) and microsatellite-stable disease, a phase III trial found.

Median overall survival with the PD-L1 inhibitor atezolizumab (Tecentriq) plus MEK inhibitor cobimetinib (Cotellic) was no better than treatment with regorafenib (Stivarga) for these patients (8.9 vs 8.5 months; HR 1.00, 95% Cl 0.73-1.38, P=0.99), reported Fortunato Ciardiello, MD, PhD, of Università degli Studi della Campania Luigi Vanvitelli in Naples, Italy, and colleagues.

And with a median overall survival of 7.1 months, atezolizumab alone was numerically worse than regorafenib (HR 1.19, 95% Cl 0.83-1.71, P=0.34), the researchers wrote in Lancet Oncology.

Median progression-free survival was 1.9 months in each of the atezolizumab arms versus 2.0 months in the regorafenib arm, and objective responses occurred in 3% of patients treated with atezolizumab-cobimetinib and in 2% of patients treated with each of the single agents.

“Although many patients with metastatic colorectal cancer who have tumors with high microsatellite instability benefit from clinical improvement after immune checkpoint inhibitor therapy, patients with microsatellite-stable tumors do not,” Ciardiello’s group wrote.

Only about 3% to 5% of CRC patients have microsatellite instability, a genetic marker for immunotherapy response that led to the FDA approval of the anti-PD-1 agents pembrolizumab (Keytruda) and nivolumab (Opdivo) and the anti–CTLA-4/PD-1 combination of ipilimumab (Yervoy) plus nivolumab for all solid tumor patients who harbor this genetic abnormality and have previously been treated with chemotherapy.

Mouse models of cobimetinib showed anti-tumor activity “while promoting the effector phenotype and longevity of tumor-infiltrating CD8+ T cells,” and an anti-MEK/PD-L1 combination had a synergistic effect that led to durable treatment responses and complete regression in some cases. A phase Ib trial that reported objective responses in 8% of CRC patients with microsatellite stable disease led to development of the phase III IMblaze370 trial.

“Despite the rationale supported by preclinical data, our results suggest that dual inhibition of the PD-L1 immune checkpoint and MAPK-mediated immune suppression is insufficient to generate anti-tumor immune responses in immune-excluded tumors, such as microsatellite-stable metastatic colorectal cancer,” the authors wrote. “This failure to generate a response could be because of alternative mechanisms to bypass the inhibition of the MAPK pathway by a MEK inhibitor.”

In an editorial that accompanied the study, Francesco Sclafani, MD, of the Institut Jules in Brussels, said the findings appear to put an end to the suggestion that MEK inhibition can overcome immune resistance in CRC patients with microsatellite-stable disease.

“There is great disappointment for the negative results of the IMblaze370 trial because of the scientific interest and general enthusiasm for the underlying biological rationale and supportive preliminary clinical findings,” he wrote. “Dwelling on potential reasons for such an unexpected failure is therefore imperative.”

Sclafani noted that the immunomodulatory effects of MEK inhibition are not actually a settled matter, with some data reporting “suppression of T lymphocyte proliferative response and antigen-specific expansion and impairment of antigen processing by dendritic cells,” which could account for the trial’s negative findings.

He also questioned the trial’s lack of a biomarker strategy and said that heterogeneous tumor characteristics in microsatellite-stable CRC may require “distinct immunomodulatory strategies” to restore immunogenicity and generate anti-tumor immune responses.

The investigators noted that a limitation of the study was that it was not designed to examine patient subgroups that may have been more likely to respond to the combination therapy.

From 2016 to 2017, the IMblaze370 study randomized 363 adult CRC patients 2:1:1 to the combination of 840-mg atezolizumab (IV every 2 weeks) plus 60-mg oral cobimetinib daily (days 1-21 of 28-day cycles), 1200-mg atezolizumab monotherapy (IV every 3 weeks), or 160-mg regorafenib monotherapy (days 1-21 of 28-day cycles). Patients were eligible if they had an Eastern Cooperative Oncology Group performance status of 0-1 and had progressed or were intolerant of ≥2 prior lines of systemic therapy. Enrollment of patients with microsatellite instability–high CRC was allowed, but capped at 5%.

Grade 3/4 adverse events (AEs) in the combination arm were twice as frequent as in the atezolizumab monotherapy arm (61% vs 31%, respectively), but similar to the regorafenib arm (58%). Common grade 3/4 AEs (>5%) in the combination arm included diarrhea (11%), increased blood creatine phosphokinase (7%), and anemia (6%).

Serious AEs occurred in 40% of patients in the combination arm versus 23% with regorafenib and 17% with atezolizumab alone. There were two therapy-related deaths with the combination arm due to sepsis and one in the regorafenib arm due to intestinal perforation.

The study was funded by Roche/Genentech.

Ciardiello disclosed financial relationships with Roche/Genentech, Merck Serono, Pfizer, Amgen, Servier, Lilly, Bayer, Bristol-Myers Squibb, and Celgene. Co-authors reported relationships with Roche/Genentech and various other industry entities.

Other posts on the correlation of Microsatellite Instability with PDL1 efficacy on this Open Access Journal include:

Collaboration With Bristol Myers Squib Led to Successful Launch of Ono Pharmaceutical’s Cancer Immune Therapy (Opdivo®)

Immunotherapy Resistance Rears Its Ugly Head: PD-1 Resistant Metastatic Melanoma and More

First Drug in Checkpoint Inhibitor Class of Cancer Immunotherapies has demonstrated Superiority over Standard of care in the treatment of First-line Lung Cancer Patients: Merck’s Keytryda



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