Immune vulnerabilities of mutant KRAS in pancreatic cancer

Abstract

The 40-year desire to target mutant KRAS (mKRAS) therapeutically is being realized with more and more broadly applicable and tumor-specific small molecular inhibitors. Immunologically, mKRAS has equal desirability as a target. Tumor KRAS signaling plays a large role in shaping the immunosuppressive nature of the tumor microenvironment, especially in pancreatic cancer, leaving mKRAS inhibitors with potentially powerful immune modulatory capabilities that could be exploited in immune-oncology combinations. mKRAS is itself an immunological antigen, a “shared neo-epitope” linked to the oncogenic process, validated biochemically and immunologically. Novel approaches in the clinic are taking advantage of the fact that mKRAS peptides are naturally processed and presented in tumors by MHC.

Pancreatic cancer and its driving oncogene mutant KRAS

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of US cancer-related deaths by 2030 [1], and despite therapeutic progress, the 5-year overall survival rate for PDAC is only 12% [2] largely due to insufficient early detection and poorly effective treatment strategies of advanced disease. First-line treatment for patients with metastatic pancreatic cancer remains combination chemotherapy, which has relatively short durability and high toxicity [3, 4]. Despite successes in patients with other cancers, immunotherapies, such as immune checkpoint antibodies, have minimal if any efficacy in PDAC as single-agents [5, 6] and mixed results when combined with chemotherapy [7].

Once thought to be undruggable, mutant Kirsten Ras (mKRAS) has become an increasingly tractable therapeutic target in patients with pancreatic cancer [8]. Oncogenic, activating KRAS mutations are present in >90% of PDAC cases [9]. KRAS is a GTPase that regulates proliferation and survival, among other cell functions, and is rendered constitutively active by genetic point mutations [10]. mKRAS is an ideal drug target in PDAC for several reasons. First, KRAS mutations initiate the formation of pre-cancerous lesions of the pancreas, termed pancreatic intraepithelial neoplasia (PanIN), and drive the development and growth of invasive carcinomas. Second, mutations in the KRAS gene are specific to tumor cells, limiting the potential off-target activity of any anti-mKRAS therapy. Lastly, the high prevalence of KRAS mutations in PDAC gives rise to a large patient population that can benefit from mKRAS treatments. In this review, we discuss how work from our group and many others has demonstrated that mKRAS shapes the tumor immune microenvironment (TME), can be targeted with small molecule inhibitors that engender immunological effects, and is a neoantigen in PDAC.

The KRAS oncogene orchestrates the pancreatic immune microenvironment

Mouse models of PDAC suggest that tumors arise in an “immune privileged” niche in which immunosuppression is a primary, rather than secondary, event. In the classic immunoediting theory, tumor cells are initially eliminated until immunosuppressive pathways are activated [11]. However, dysfunctional dendritic cells, suboptimal T cell priming, and high levels of immunosuppression in PanINs suggest that PDAC diverges from the immunoediting theory because of its immunologically “cold” status even at the earliest stages of tumorigenesis [12–16].

mKRAS, also referred to as oncogenic KRAS here, promotes the accumulation of immunosuppressive cells that exclude cytotoxic T cells (Figure 1), as demonstrated in autochthonous genetically engineered mouse models of PDAC that recapitulate the histopathological and clinical features of human PDAC. These models include the Kras^LSL-G12D/+ Pdx1-Cre (KC) and Kras^LSL-G12D/+ Trp53^LSL-R172H/+ Pdx1-Cre (KPC) mice [17, 18]. Using KC mice, we demonstrated that PanIN formation is accompanied by an influx of immunosuppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). This infiltration of immunosuppressive cells is accompanied by a dearth of activated, effector T cells [19]. Oncogenic KRAS upregulates tumor cytokine expression, such as GM-CSF, which leads to the accumulation of MDSCs [20, 21]. These MDSCs actively participate in the exclusion of CD8+ T cells from the PanIN and tumor microenvironments, because their depletion or the neutralization of GM-CSF enhances T cell infiltration. In an inducible mKRAS model with pancreatitis, KRAS expression causes PanIN infiltration of CD4+ T cells (most likely Tregs), which can also regulate inflammatory cell infiltration and inhibit CD8+ T cell activation [22]. mKRAS signaling plays a critical role in recruiting immunosuppressive cells and potentially even converting cells to such a phenotype [23].

Figure 1. Mutant (m)KRAS establishes an immunosuppressive microenvironment in the pancreas throughout tumorigenesis.

Expression of mKRAS leads to the recruitment of immunosuppressive cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), that inhibit CD8+ T cell infiltration and function. GM-CSF release is upregulated by mKRAS and directly modulates MDSC accumulation. mKRAS signaling in pre-cancerous, neoplastic epithelial cells promotes cancer-associated fibroblast (CAF) accumulation and expression of cytokines (CXCL1, Il-6, IL-33, and SAA3) that support immunosuppressive myeloid cell populations. mKRAS also primes pancreatic neoplastic and tumor cells to respond to pro-tumorigenic cytokines released by inflammatory immune cells. mKRAS induces expression of IL-17R and type I cytokine receptors, IL-4Rα and IL-13Rα1, enabling the neoplastic/tumor cells to respond to growthpromoting cytokines released by Th17 and Th2 cells, respectively. Increased IL-6 production following KRAS mutation helps maintain a pool of Th17 cells in the pancreatic microenvironment. This figure was made using Biorender.com. Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; CXCL1, C-X-C motif chemokine ligand 1; IL-6, interleukin-6; IL-33, interleukin-33; SAA3, serum amyloid a3; IL-17(R), interleukin-17 (receptor); IL-4(Rα), interleukin-4 (receptor α); IL-13(Rα1) interleukin-13 (receptor α 1); Th17, T helper 17; Th2, T helper 2.

The desmoplasia characteristic of PDAC includes cancer-associated fibroblasts (CAFs), which are immune-modulating and influenced by mKRAS signaling [24]. In the inducible mouse model of KRAS^G12D, oncogenic KRAS promotes infiltration, activation, and reprogramming of CAFs at PanIN stages (Figure 1). Specifically, mKRAS signaling in transforming epithelial cells extrinsically programs CAFs to produce cytokines (i.e. IL-33 and IL-6) that regulate immunosuppressive myeloid cells [25]. In established PDAC tumors, CAFs, depending on the subtype, can be immune-suppressive (antigen-presenting and LRRC15+ CAFs) [26, 27] or immune-enhancing (T CAFs) [28]. The exact immune-mediating function of CAFs in PDAC is likely also based on the stage of carcinogenesis.

T helper 17 (Th17) cells have a clearly defined role in inflammation and autoimmunity, but their involvement in cancer and tumor immunity is more nuanced [29]. Oncogenic KRAS expression drives the production of IL-6 [30, 31], a polarizing cytokine for Th17 cells, and helps orchestrate the infiltration of Th17 cells [32]. mKRAS signaling also upregulates IL-17R on PanIN epithelial cells in a cell-autonomous manner, and Th17 cells release IL-17 that promotes PanIN formation and progression [32]. A similarly constructed pathway exists involving Th2 cells. In an inducible KRAS^G12D PDAC model, mKRAS increases expression of type I cytokine receptors, such as IL-4Rα and IL-13Rα1, which recognize IL-4 and IL-13 secreted by PanIN and tumor infiltrating Th2 cells. These cytokines are tumor-promoting as they upregulate MYC through the JAK1-STAT6 pathway [33]. In both of these examples, downstream effects of mutant KRAS expression give neoplastic epithelial or tumor cells the ability to respond to pro-tumorigenic signals coming from the inflammatory immune cell milieu (Figure 1).

Studies that inactivate KRAS reaffirm the immune modulatory role of the oncogene and tantalizingly suggest that targeting mKRAS therapeutically might synergize with immunotherapy approaches in PDAC. In the inducible KRAS^G12D model, turning KRAS^G12D off repolarizes macrophages away from an immunosuppressive M2 phenotype and decreases the number of pancreatic-infiltrating MDSCs [25, 34]. In a CRISPR/Cas9 experimental system that knock-outs (KO) KRAS^G12D in a PDAC cell line [35], KRAS KO orthotopic tumors exhibit polarization of TAMs to an anti-tumor M1 state and increased infiltration of CD4+ and cytotoxic CD8+ T cells. These T cells are more active and produce IFNγ. Among other effects in the TME, IFNγ induces tumor cell apoptosis, angiogenesis inhibition, and activation of M1 macrophages, which are capable of specifically killing tumor cells [36–38]. Interestingly, these KRAS KO tumor cells have increased expression of major histocompatibility complex (MHC), consistent with improved immunogenicity [35]. Evidently, targeting mKRAS can reverse the immunosuppression inherent to PDAC and possibly augment immunotherapies.

Although knocking out mKRAS in PDAC tumors in vivo has been attempted [39], the predominant approach to blocking oncogenic KRAS expression in a therapeutic setting is through small molecule inhibitors (Table 1). The recent identification and characterization of KRAS^G12C inhibitors have shown that drugging mKRAS is possible [40–43]. These KRAS^G12C inhibitors exhibit therapeutic efficacy in various solid tumors, including pancreatic cancer [44–47]; however, in PDAC, KRAS^G12C mutations are present in only 1% of patients, whereas KRAS^G12D represents ~40% of all KRAS mutations [48]. We recently investigated the efficacy of a novel, non-covalent inhibitor of KRAS^G12D (MRTX1133) in immunocompetent mouse models of PDAC [49], as the initial studies interrogated the drug in immune deficient hosts [50, 51].

Table 1.

Advantages and drawbacks of mKRAS targeting therapeutics in pancreatic cancer^a

Anti-mKRAS therapy	Advantages	Drawbacks
Small molecule inhibitors	Potent anti-tumor activity in models and patients ↑ MHC expression ↓ Immunosuppressive cells ↑ Effector T cell infiltration and functionality Potential synergy with immunotherapies	Development of resistance Potential impact on normal cells
Vaccines	Pooled peptide/mRNA vaccines can be made to cover several variants Can induce long-lasting anti-tumor immunity	Must overcome immunosuppression in the TME
ACT with engineered TCRs	Promising early clinical case reports Can induce long-lasting anti-tumor immunity	Must overcome immunosuppression in the TME MHC restricted Dependent on sufficient antigen density and MHC expression Highly personalized so costly and laborious to produce
Bispecific antibodies	Can have very high affinity for mKRAS without compromising specificity Personalized yet off-the-shelf	MHC restricted Dependent on sufficient antigen density and MHC expression
Hapimmune	Combines benefits of inhibitor and TCR-based therapies: direct inhibition, favorable immunomodulation, and immune-mediated killing	Dependent on sufficient antigen density and MHC expression

^aAbbreviations: ACT, adoptive T cell therapy; HLA, human leukocyte antigen; MHC, major histocompatibility complex; mKRAS, mutant KRAS; TCR, T cell receptor; TME, tumor microenvironment.

MRTX1133 shows robust efficacy in subcutaneous, orthotopic, and autochthonous models. In fact, we have never observed such pronounced and lasting tumor regressions in KPC mice in our many years of testing anti-tumor agents in this model. Interestingly, the drug’s full efficacy is dependent on T cells, and inhibiting mKRAS favorably alters the PDAC tumor immune microenvironment and improves anti-tumor immunity. MRTX1133 leads to increased expression of MHC class I on tumor cells, increased αSMA+ fibroblasts, repolarization of macrophages to an M1 phenotype, decreased proportion of MDSCs, and increased infiltration of T cells. Moreover, these T cells are more proliferative, activated, and cytotoxic [49]. Our results suggest that mKRAS inhibitors could not only reverse the immunosuppression constructed by oncogenic KRAS expression but also induce a “vaccine effect” by which T cells are primed to restrain future tumor regrowth. In all, KRAS^G12D inhibitors have immense promise to treat a large proportion of PDAC patients and open the door for new combinatorial treatment strategies.

Preclinical studies suggest synergy between KRAS^G12C inhibitors and anti-PD-1 therapy, although none was performed in the context of PDAC [43, 52, 53]. Clinical trials are underway to test KRAS^G12C inhibitors in combination with immune checkpoint blockade in non-small cell lung cancer patients (NCT04185883 and NCT04613596), and early results indicate manageable adverse events and encouraging efficacy [54]. Beyond immune checkpoint inhibitors, other immune agents that may improve T cell priming, such as Flt3L and agonistic CD40 [13, 55], are potential combination partners in PDAC, as are vaccines and adoptive T cell therapies, both of which will be discussed later in this article. One possible combinatorial strategy involves the “hapimmune” concept (Table 1). The cysteine made available by the KRAS^G12C mutation enables the production of covalent inhibitors. These inhibitors bind mKRAS; mKRAS-inhibitor complexes are processed and presented in the context of MHC; then, the drug-peptide conjugates can be targeted with bispecific antibodies and potentially T cell receptors (TCRs) [56, 57]. The development of covalent (and non-covalent) inhibitors for other mKRAS variants, especially KRAS^G12D, would encourage further testing of the hapimmune approach with more relevance to PDAC.

Vaccination against mutant KRAS

The specificity of oncogenic KRAS to PDAC cells and its importance in tumor growth makes the mutated protein an attractive tumor neoantigen that can be targeted by T cells. The discovery of naturally occurring mKRAS-specific T cells opened the possibility for vaccination and adoptive T cell therapy strategies. Some of the earliest studies observed KRAS^G12V-specific CD4+ T cells in healthy individuals [58] and KRAS^G13D-specific CD4+ and CD8+ T cells in a colorectal cancer patient [59]. Another analysis found that a natural reservoir of mKRAS-specific CD4+ and CD8+ T cells exists in human leukocyte antigen (HLA)-A*02-positive PDAC patients [60]. Following stimulation, these CD8+ T cells are able to kill KRAS^G12V-mutated pancreatic cancer cells in an HLA-restricted manner. Identification of naturally occurring anti-mKRAS T cell responses prompted a series of mKRAS vaccine trials.

mKRAS vaccines have been shown to induce mKRAS-specific immunity but their efficacy and the best setting for use remains uncertain (Table 1). A pioneering trial vaccinated a small cohort of pancreatic cancer patients with peripheral blood mononuclear cells (PBMCs) loaded with synthetic mKRAS peptides [61]. Although no therapeutic benefit was observed, oncogenic KRAS-specific T cells were induced by vaccination in a couple of patients, and in one of the patients, these T cells were able to kill autologous tumor cells in an HLA-restricted manner in vitro [62]. In another study using PBMCs pulsed with mKRAS peptides, only one out of nine pancreatic cancer patients responded to the vaccine [63]. mKRAS peptide vaccines have also been tested with adjuvants, such as GM-CSF. A considerable number of patients with advanced PDAC who received synthetic mKRAS peptide(s) and GM-CSF demonstrated an immunological response [64]. Moreover, a subset of these immune responders had stable disease following treatment, and responders exhibited a survival benefit when compared to those that did not respond to vaccination. In the adjuvant setting, peptide-based vaccination against mKRAS has shown more clinical promise but the therapeutic efficacy has still not been confirmed [65–67]. Interestingly, one study found memory T cell responses in patients up to 9 years following mKRAS peptide vaccine adjuvant therapy [67]. Recently, a phase I clinical trial (NCT03948763) was initiated to test an anti-mKRAS mRNA-based vaccine (mRNA-5671/V941) with or without anti-PD-1 therapy in patients with advanced or metastatic PDAC, non-small cell lung cancer, or colorectal cancer. Enrollment criteria include a confirmed KRAS mutation (G12D, G12V, G13D, or G12C) and HLA-A*11:01 and/or HLA-C*08:02 positivity. Another trial (NCT03953235) is investigating an adenovirus and self-amplifying mRNA mKRAS vaccine regimen in combination with immune checkpoint blockade (ICB) in PDAC and other solid tumors. Future mKRAS vaccine studies in PDAC should consider combination approaches with immunotherapies other than ICB, which exhibits limited efficacy in the disease.

Given that KRAS mutations are usually the initial and driving mutation in PanIN formation and PDAC development, vaccinating high-risk – but healthy – individuals offers a promising approach to preventing, or intercepting, PDAC. Attenuated Listeria monocytogenes (LM) engineered to express KRAS^G12D in combination with a T_reg-depleting regimen prolongs survival and delays PanIN development when given to KPC mice bearing early-stage, but not late-stage, PanINs [68]. These data provide evidence that intervening in the natural history of PDAC using a mKRAS-based therapy is feasible. A current phase 1 clinical trial (NCT05013216) is testing a pool of mKRAS peptides as a vaccine for individuals who are at high risk of developing PDAC but who have not done so yet. Enrollment criteria include a family history of pancreatic cancer and/or predisposing germline mutations as well as imaging of a pancreatic abnormality, such as a cyst. While a potential therapeutic benefit for such an approach will not reveal itself for many years, determining whether mKRAS-targeting T cell responses can be generated at precancerous, neoplastic stages is important.

It seems logical that mKRAS vaccination will have to be used and tested in combination with other therapies, beyond immune checkpoint blockade, that manipulate the immunosuppression inherent to PDAC. Oncogenic KRAS constructs a pancreatic microenvironment that inhibits a natural anti-tumor or anti-PanIN immune response. Thus, even if a vaccine could stimulate the expansion of mKRAS-specific T cells, there is no guarantee that those T cells could overcome the immunosuppressive barriers set in place in vivo. Indeed, for a vaccine to have efficacy in PanIN-bearing KPC mice, a T_reg-depleting treatment that is not readily translatable is needed [68]. Perhaps these vaccines will prove most efficacious in the adjuvant setting when tumor burden is low [69]; otherwise, a focus could be put on interrogating mKRAS vaccines in combination with mKRAS inhibitors and/or immunotherapies proven to remodel the PDAC tumor immune microenvironment.

Targeting mutant KRAS using TCR-based therapies

A growing body of work has identified HLA class I-restricted mKRAS epitopes and TCRs that recognize these epitopes. T cells engineered to express these TCRs show therapeutic efficacy in preclinical mouse models. For example, mKRAS-specific TCRs have been isolated from HLA-A*11:01 transgenic mice immunized with KRAS^G12D/V peptides [70]. Human T cells transduced with the KRAS^G12D-reactive TCR slow tumor growth and prolong survival in immunodeficient mice implanted with a human HLA-A*11:01- and KRAS^G12D-positive pancreatic cancer cell line. We and our colleagues used a bioinformatic, biochemical, and proteomic approach to characterize mKRAS G12 epitopes that are processed and then presented with high affinity and stability by three HLA class I complexes: HLA-A*03:01, HLA-A*11:01, and HLA-B*07:02 [71]. TCRα/β pairs were then isolated and sequenced from CD8+ T cells that recognized immunogenic mKRAS epitopes. CD8+ T cells transduced with TCRs specific for KRAS^G12V in the context of HLA-A*03:01 or HLA-A*11:01 exhibit lytic activity against HLA class I matched human tumor cell lines and have potent anti-tumor activity when adoptively transferred into immunodeficient mice harboring metastatic lung cancer. A similar pipeline was taken (1) to identify even more mKRAS neoantigens (4 KRAS mutations across 9 common HLA class I alleles) that are endogenously processed and presented and (2) to broaden the repertoire of mKRAS peptide-HLA class I complexes that are known to be immunogenic [72]. mKRAS-reactive TCRs can also be screened from tumor-infiltrating and peripheral blood lymphocytes of cancer patients with KRAS-mutated tumors [73]. Once identified, mKRAS TCRs can form the basis of adoptive T cell therapy and also bispecific, T cell engaging molecules that fuse TCRs or TCR-mimic single-chain variable fragments (scFvs) to an anti-CD3 scFv, as has been previously shown [74, 75] (Table 1).

Initial clinical observations have demonstrated the promise of TCR T cell therapies targeting mKRAS. In one case, a colon cancer patient showed a natural T cell response to KRAS^G12D [76]. Upon infusion of autologous T cells engineered to express an HLA-C*08:02-restricted TCR specific for KRAS^G12D, the patient had a 9-month partial response and regressions of lung metastases. In a subsequent case, a patient with metastatic pancreatic cancer was given autologous T cells transduced with KRAS^G12D-specific, HLA-C*08:02-restricted TCRs [77]. The lung metastases of this patient regressed. These studies serve as proof-of-concept for the therapeutic potential for mKRAS TCR therapy and provide promise for larger clinical trials (NCT03190941 and NCT03745326).

To bring mKRAS T cell therapies to a larger patient population, identification of more mKRAS epitope and HLA class I peptidomes as well as TCRs that recognize such complexes will be critical. While it has been shown that mKRAS neoantigens are presented by some of the most common HLA class I alleles, such as HLA-A*03:01 and HLA-A*11:01 [70–72], there are many other HLA class I molecules that, to our knowledge, have not been thoroughly investigated in terms of mKRAS epitopes. Established pipelines for mKRAS neoantigen discovery can be used to comprehensively interrogate both HLA class I and II alleles of all frequencies to find which ones naturally present mKRAS epitopes and which peptide-HLA complexes are immunogenic [78].

Even as more candidate mKRAS neoantigens are found, the low abundance of these neoantigens presents a challenge for TCR-based therapies. For example, it has been estimated that the number of KRAS^G12V peptides presented on various cancer cell lines is no greater than ~100 per cell and can be as low as ~10 per cell [71, 72, 75]. The activity of TCR-engineered cells correlates with mKRAS peptide-HLA complex abundance [71], so elucidating ways to increase activity will be important. Increasing the avidity of mKRAS TCRs is one such strategy. In fact, the affinity of a KRAS^G12D-specific TCR was enhanced one million-fold without losing any specificity for the mutated variant over the wild-type one [74].

TCR-based therapies, of course, are dependent on peptide-MHC expression, which can be problematic. For the patient with metastatic colon cancer noted above who was given mKRAS-specific T cells, the one lung lesion that progressed lost expression of the MHC molecule presenting KRAS^G12D [76]. Pancreatic cancer has established mechanisms that decrease antigen presentation, such as the downregulation of MHC class I expression [79, 80]. Autophagy has been shown to selectively degrade MHC class I molecules in PDAC and thus likely contributes to the deficient antigen presentation in this malignancy [81]. Inhibiting autophagy rescues MHC class I expression and enhances the efficacy of immune checkpoint blockade in a mouse model of PDAC. Combining autophagy inhibitors with mKRAS TCR-engineered T cells is an intriguing therapeutic avenue, as the autophagy inhibitors could increase the number of targets for T cell therapy.

Concluding remarks

mKRAS has long been an attractive therapeutic target in pancreatic cancer given its ubiquity in the patient population, its specificity to the tumor, and its important role in tumor development. Recent work has shown that (1) mKRAS is druggable with small molecule inhibitors and (2) the oncogenic protein is an immunological target itself. mKRAS inhibitors may have immunologic consequences, reversing mKRAS-constructed immunosuppression in the pancreatic microenvironment and cooperating with T cell immunity for full effect. Complimentarily, vaccines and T cell receptor-based therapies are being developed to induce anti-mKRAS immune responses. Nonetheless, many knowledge gaps and questions remain (see Outstanding questions), such as the clinical efficacy of and proper setting for mKRAS vaccines. Future work must focus on identifying potent and viable treatment combinations (i.e. mKRAS inhibitors with immune checkpoint blockade or mKRAS inhibitors with TCR therapies), as PDAC is unlikely to be controlled with a monotherapy. Resistance to the various mKRAS-based therapies is another important topic that needs to be addressed. While the exact clinical role of these treatments remains to be determined, we suggest that drugging mKRAS and treating patients with pancreatic cancer more broadly can be approached through an immunological lens.

Outstanding Questions.

• Given that mKRAS inhibitors increase MHC expression and reduce immunosuppression, does blocking mKRAS pharmacologically lead to the expansion and infiltration of mKRAS-specific T cells? Can these inhibitors synergize with mKRAS vaccines and TCR-based therapies?

• Can mKRAS-targeted therapies be administered to high risk, but otherwise healthy, individuals to intercept tumorigenesis? Will the efficacy of such therapies and their impact on the immune microenvironment vary in different settings (i.e. PanIN versus invasive carcinoma)?

• What immunotherapies are best suited to be used in combination with mKRAS-specific treatments in the context of PDAC?

• What is the best setting for mKRAS vaccines – cancer interception, adjuvant therapy, or advanced disease?

• How will resistance to anti-mKRAS TCR-based therapies manifest in pancreatic cancer patients?

Highlights.

The KRAS oncogene is mutated in the vast majority of tumors of pancreatic cancer patients and directly promotes tumor initiation and progression as well as an immunosuppressive microenvironment, but until recently mutant KRAS (mKRAS) was considered undruggable.

Novel mKRAS inhibitors have shown therapeutic efficacy in preclinical models and clinical trials for numerous KRAS-mutated cancers. These inhibitors ameliorate the immunosuppression that is characteristic of pancreatic cancer and thus are logical candidates to be tested in combination with immunotherapies.

mKRAS is also immunogenic, and endogenous anti-mKRAS T cells exist. T cells engineered with mKRAS-specific T cell receptors have already shown early clinical promise, and next-generation mKRAS vaccines are being studied.

As this emerging field rapidly develops, we suggest that a significant component to “drugging KRAS” may be immunological.